1h-benzimidazole-4-carboxamides substituted with phenyl at the 2-position are potent parp inhibitors

ABSTRACT

Compounds having formula (I) 
     
       
         
         
             
             
         
       
     
     inhibit the PARP enzyme and are useful for treating a disease or a disorder associated with PARP. Also disclosed are pharmaceutical compositions comprising compounds having formula (I), methods of treatment comprising compounds having formula (I), and methods of inhibiting the PARP enzyme comprising compounds having formula (I).

This application claims priority to U.S. Provisional Application Ser.No. 60/721,683, filed Sep. 29, 2005.

FIELD OF THE INVENTION

This invention relates to 1H-benzimidazole-4-carboxamides, theirpreparation, and their use as inhibitors of the enzymepoly(ADP-ribose)polymerase for the preparation of drugs.

BACKGROUND OF THE INVENTION

Poly(ADP-ribose)polymerase (PARP) or poly(ADP-ribose)synthase (PARS) hasan essential role in facilitating DNA repair, controlling RNAtranscription, mediating cell death, and regulating immune response.These actions make PARP inhibitors targets for a broad spectrum ofdisorders. PARP inhibitors have demonstrated efficacy in numerous modelsof disease, particularly in models of ischemia reperfusion injury,inflammatory disease, degenerative diseases, protection from adverseeffects of cytoxic compounds, and the potentiation of cytotoxic cancertherapy. PARP has also been indicated in retroviral infection and thusinhibitors may have use in antiretroviral therapy. PARP inhibitors havebeen efficacious in preventing ischemia reperfusion injury in models ofmyocardial infarction, stroke, other neural trauma, organtransplantation, as well as reperfusion of the eye, kidney, gut andskeletal muscle. Inhibitors have been efficacious in inflammatorydiseases such as arthritis, gout, inflammatory bowel disease, CNSinflammation such as MS and allergic encephalitis, sepsis, septic shock,hemmorhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors havealso shown benefit in several models of degenerative disease includingdiabetes (as well as complications) and Parkinsons disease. PARPinhibitors can ameliorate the liver toxicity following acetominophenoverdose, cardiac and kidney toxicities from doxorubicin and platinumbased antineoplastic agents, as well as skin damage secondary to sulfurmustards. In various cancer models, PARP inhibitors have been shown topotentiate radiation and chemotherapy by increasing cell death of cancercells, limiting tumor growth, decreasing metastasis, and prolonging thesurvival of tumor-bearing animals.

SUMMARY OF THE INVENTION

In one embodiment, this invention comprises compounds having formula (I)

or a salt thereof, wherein

R₁, R₂, and R₃ are independently selected from the group consisting ofhydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,NR_(A)R_(B), and (NR_(A)R_(B))carbonyl;

each R₄ is independently selected from the group consisting of hydrogen,halogen, alkyl, and haloalkyl;

m is 4;

Z is a bond or alkylenyl;

A is a nonaromatic 5 or 6-membered ring that contains 1 or 2 nitrogenatoms and, optionally, one sulfur or oxygen atom, wherein A is attachedto Z through a carbon atom, and wherein the nonaromatic ring isoptionally substituted with 1, 2, or 3 substituents selected from thegroup consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkynyl,aryl, arylalkyl, carboxy, cycloalkyl, cycloalkylalkyl, cyano,haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl,heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclesulfonyl,hydroxy, hydroxyalkyl, NR_(C)R_(D), (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,(NR_(C)R_(D))sulfonyl, and oxo; and

R_(A), R_(B), R_(C), and R_(D) are independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, and alkycarbonyl.

DETAILED DESCRIPTION OF THE INVENTION

In another embodiment, this invention comprises compounds having formula(I)

or a salt thereof, wherein

R₁, R₂, and R₃ are independently selected from the group consisting ofhydrogen and halogen;

each R₄ is independently selected from the group consisting of hydrogen,halogen, and haloalkyl;

m is 4;

Z is a bond or alkylenyl;

A is a nonaromatic 5 or 6-membered ring that contains 1 nitrogen atom,wherein A is attached to Z through a carbon atom, and wherein thenonaromatic ring is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of alkoxycarbonyl, alkyl, arylalkyl,cycloalkyl, cycloalkylalkyl, and heterocyclealkyl.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein Z is abond.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein Z isalkylenyl.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein A isselected from the group consisting of

each R₅ is independently selected from the group consisting of alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano,haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl,heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and (NR_(C)R_(D))sulfonyl;

R₆ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl,arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl,heteroaryl, heteroarylalkyl, hydroxyalkyl, (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl, and(NR_(C)R_(D))sulfonyl;

R_(C) and R_(D) are independently selected from the group consisting ofhydrogen and alkyl; and n is 0, 1, 2, or 3.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein

Z is a bond;

A is selected from the group consisting of

each R₅ is independently selected from the group consisting of alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano,haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl,heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and (NR_(C)R_(D))sulfonyl;

R₆ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl,arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl,heteroaryl, heteroarylalkyl, hydroxyalkyl, (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl, and(NR_(C)R_(D))sulfonyl;

R_(C) and R_(D) are independently selected from the group consisting ofhydrogen and alkyl;

and n is 0, 1, 2, or 3.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein A isselected from the group consisting of

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein A isselected from the group consisting of

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein R₁, R₂,and R₃ are hydrogen.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein R₂ ishalogen.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), wherein each R₄ ishydrogen.

In another embodiment, this invention comprises a pharmaceuticalcomposition comprising a compound having formula (I), or a salt thereof,and therapeutically acceptable carrier.

In another embodiment, this invention comprises a method of inhibitingPARP in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having formula (I) or a salt thereof.

In another embodiment, this invention comprises a method of treatingcancer in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having formula (I) or a salt thereof.

In another embodiment, this invention comprises a method for decreasingtumor volume in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatingleukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomasof the breast, or cervical carcinomas in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula (I) or a salt thereof.

In another embodiment, this invention comprises a method of potentiationof cytotoxic cancer therapy in a mammal comprising administering theretoa therapeutically acceptable amount of a compound having formula (I) ora salt thereof.

In another embodiment, this invention comprises a method of potentiationof radiation therapy in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatingischemia reperfusion injury associated with, but not limited to,myocardial infarction, stroke, other neural trauma, and organtransplantation, in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of reperfusionincluding, but not limited to, reperfusion of the eye, kidney, gut andskeletal muscle, in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatinginflammatory diseases including, but not limited to, arthritis, gout,inflammatory bowel disease, CNS inflammation, multiple sclerosis,allergic encephalitis, sepsis, septic shock, hemmorhagic shock,pulmonary fibrosis, and uveitis in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formula(I) or a salt thereof.

In another embodiment, this invention comprises a method of treatingimmunological diseases or disorders such as rheumatoid arthritis andseptic shock in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatingdegenerative disease including, but not limited to, diabetes andParkinsons disease, in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatinghypoglycemia in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatingretroviral infection in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatingliver toxicity following acetominophen overdose in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula (I) or a salt thereof.

In another embodiment, this invention comprises a method of treatingcardiac and kidney toxicities from doxorubicin and platinum basedantineoplastic agents in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a method of treatingskin damage secondary to sulfur mustards in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula (I) or a salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament forinhibiting the PARP enzyme in a mammal in recognized need of suchtreatment.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament forinhibiting tumor growth in a mammal in recognized need of suchtreatment.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating cancer in a mammal in recognized need of such treatment.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating leukemia, colon cancer, glioblastomas, lymphomas, melanomas,carcinomas of the breast, or cervical carcinomas in a mammal in a mammalin recognized need of such treatment.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament forpotentiation of cytotoxic cancer therapy in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula (I) or a salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament forpotentiation of radiation in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating ischemia reperfusion injury associated with, but not limitedto, myocardial infarction, stroke, other neural trauma, and organtransplantation, in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating reperfusion including, but not limited to, reperfusion of theeye, kidney, gut and skeletal muscle, in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula (I) or a salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating inflammatory diseases including, but not limited to, arthritis,gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis,allergic encephalitis, sepsis, septic shock, hemmorhagic shock,pulmonary fibrosis, and uveitis in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formula(I) or a salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating immunological diseases or disorders such as rheumatoidarthritis and septic shock in a mammal comprising administering theretoa therapeutically acceptable amount of a compound having formula (I) ora salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating degenerative disease including, but not limited to, diabetesand Parkinsons disease, in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating hypoglycemia in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating retroviral infection in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formula(I) or a salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating liver toxicity following acetominophen overdose in a mammalcomprising administering thereto a therapeutically acceptable amount ofa compound having formula (I) or a salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating cardiac and kidney toxicities from doxorubicin and platinumbased antineoplastic agents in a mammal comprising administering theretoa therapeutically acceptable amount of a compound having formula (I) ora salt thereof.

In another embodiment, this invention comprises a use of a compoundhaving formula (I), or a salt thereof, to prepare a medicament fortreating skin damage secondary to sulfur mustards in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula (I) or a salt thereof.

As used throughout this specification, the following terms have thefollowing meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, attached to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein, means at least one alkoxy group,as defined herein, attached to the parent molecular moiety through analkyl group, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, attached to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, attached to the parent molecular moietythrough an alkyl group, as defined herein.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, attached to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, attached to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylenyl” as used herein, means a divalent group derived froma straight or branched chain hydrocarbon of from 1 to 6 carbon atoms.Representative examples include, but are not limited to, —CH₂—,—CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂—,

The term “alkylthio” as used herein, means an alkyl group, as definedherein, attached to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkylthioalkyl” as used herein, means an alkylthio group, asdefined herein, attached to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkylthioalkylinclude, but are not limited, methylthiomethyl and 2-(ethylthio)ethyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means a phenyl group or a naphthylgroup.

The aryl groups of this invention can be optionally substituted withone, two, three, four, or five substituents independently selected fromthe group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen,heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, —NR_(E)R_(F), and(NR_(E)R_(F))carbonyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, attached to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl,1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “cyano” as used herein, means a —CN group.

The term “cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons, examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The cycloalkyl groups of this invention are optionally substituted with1, 2, 3, or 4 substituents selected from alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, oxo, —NR_(E)R_(F), and(NR_(E)R_(F))carbonyl.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, attached to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, attached to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, attached to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroarylring or a bicyclic heteroaryl ring. The monocyclic heteroaryl ring is a5 or 6 membered ring. The 5 membered ring has two double bonds andcontains one, two, three or four heteroatoms independently selected fromthe group consisting of N, O, and S. The 6 membered ring has threedouble bonds and contains one, two, three or four heteroatomsindependently selected from the group consisting of N, O, and S. Thebicyclic heteroaryl ring consists of the 5 or 6 membered heteroaryl ringfused to a phenyl group or the 5 or 6 membered heteroaryl ring is fusedto another 5 or 6 membered heteroaryl ring. Nitrogen heteroatomscontained within the heteroaryl may be optionally oxidized to theN-oxide. The heteroaryl is connected to the parent molecular moietythrough any carbon atom contained within the heteroaryl whilemaintaining proper valence. Representative examples of heteroarylinclude, but are not limited to, benzothienyl, benzoxadiazolyl,cinnolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl,isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyrrolyl, pyridinium N-oxide, quinolinyl, tetrazolyl, thiadiazolyl,thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.

The heteroaryl groups of this invention are substituted with 0, 1, 2, 3,or 4 substituents independently selected from alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,—NR_(E)R_(F), and (NR_(E)R_(F))carbonyl.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, attached to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heteroarylalkylinclude, but are not limited to, pyridinymethyl. The term “heterocycle”or “heterocyclic” as used herein, means a monocyclic or bicyclicheterocyclic ring. The monocyclic heterocyclic ring consists of a 3, 4,5, 6, 7, or 8 membered ring containing at least one heteroatomindependently selected from O, N, and S. The 3 or 4 membered ringcontains 1 heteroatom selected from the group consisting of O, N and S.The 5 membered ring contains zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. The6 or 7 membered ring contains zero, one or two double bonds and one, twoor three heteroatoms selected from the group consisting of O, N and S.The bicyclic heterocyclic ring consists of a monocyclic heterocyclicring fused to a cycloalkyl group or the monocyclic heterocyclic ringfused to a phenyl group or the monocyclic heterocyclic ring fused toanother monocyclic heterocyclic ring. The heterocycle is connected tothe parent molecular moiety through any carbon or nitrogen atomcontained within the heterocycle while maintaining proper valence.Representative examples of heterocycle include, but are not limited to,azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl.

The heterocycles of this invention are substituted with 0, 1, 2, or 3substituents independently selected from alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, nitro, —NR_(E)R_(F),(NR_(E)R_(F))carbonyl, and phenylalkoxycarbonyl.

The term “heterocyclealkyl” as used herein, means a heterocycle, asdefined herein, attached to the parent molecular moiety through an alkylgroup, as defined herein.

The term “heterocyclecarbonyl” as used herein, means a heterocycle, asdefined herein, attached to the parent molecular moiety through acarbonyl group, as defined herein.

The term “heterocyclesulfonyl” as used herein, means a heterocycle, asdefined herein, attached to the parent molecular moiety through asulfonyl group.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is attached to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “nonaromatic” as used herein, means that a 4 memberednonaromatic ring contains zero double bonds, a 5 membered nonaromaticring contains zero or one double bond, a 6, 7, or 8 membered nonaromaticring contains zero, one, or two double bonds.

The term “NR_(A)R_(B)” as used herein, means two groups, R_(A) andR_(B), which are attached to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are each independently hydrogen, alkyl,alkylcarbonyl, and cycloalkyl. Representative examples of NR_(A)R_(B)include, but are not limited to, amino, methylamino, acetylamino, andacetylmethylamino.

The term “(NR_(A)R_(B))carbonyl” as used herein, means a NR_(A)R_(B)group, as defined herein, attached to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “NR_(C)R_(D)” as used herein, means two groups, R_(C) andR_(D), which are attached to the parent molecular moiety through anitrogen atom. R_(C) and R_(D) are each independently hydrogen, alkyl,alkylcarbonyl, and cycloalkyl. Representative examples of NR_(C)R_(D)include, but are not limited to, amino, methylamino, acetylamino, andacetylmethylamino.

The term “(NR_(C)R_(D))carbonyl” as used herein, means a NR_(C)R_(D)group, as defined herein, attached to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(C)R_(D))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(NR_(C)R_(D))carbonylalkyl” as used herein, means a(NR_(C)R_(D))carbonyl group, as defined herein, attached to the parentmolecular moiety through an alkyl group, as defined herein.

The term “(NR_(C)R_(D))sulfonyl” as used herein, means a NR_(C)R_(D)group, as defined herein, attached to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(C)R_(D))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl, and(ethylmethylamino)sulfonyl.

The term “NR_(E)R_(F)” as used herein, means two groups, R_(E) andR_(F), which are attached to the parent molecular moiety through anitrogen atom. R_(E) and R_(F) are each independently hydrogen, alkyl,alkylcarbonyl, and cycloalkyl. Representative examples of NR_(E)R_(F)include, but are not limited to, amino, methylamino, acetylamino, andacetylmethylamino.

The term “(NR_(E)R_(F))carbonyl” as used herein, means a NR_(E)R_(F)group, as defined herein, attached to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(E)R_(F))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “oxo” as used herein, means a ═O moiety.

Protecting groups for NH moieties include, but are not limited to,acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene,benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc),3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl,formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl,phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl,trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl,para-toluenesulfonyl.

Compounds of this invention can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S) depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30, herebyincorporated by reference. This invention contemplates variousstereoisomers and mixtures thereof and are specifically included withinthe scope of this invention. Stereoisomers include enantiomers,diastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of this invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Compounds of this invention were named by ACD/ChemSketch version 5.06(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names which appeared to be consistent with ACDnomenclature.

Inhibition of PARP

Nicotinamide[2,5′,8-3H]adenine dinucleotide and strepavidin SPA beadswere purchased from Amersham Biosiences (UK) Recombinant HumanPoly(ADP-Ribose) Polymerase (PARP) purified from E. coli and6-Biotin-17-NAD⁺, were purchase from Trevigen, Gaithersburg, Md. NAD⁺,Histone, aminobenzamide, 3-amino benzamide and Calf Thymus DNA (dcDNA)were purchased from Sigma, St. Louis, Mo. Stem loop oligonucleotidecontaining MCAT sequence was obtained from Qiagen. The oligos weredissoloved to 1 mM in annealing buffer containing 10 mM Tris HCl pH 7.5,1 mM EDTA, and 50 mM NaCl, incubated for 5 min at 95° C., and followedby annealing at 45° C. for 45 minutes. Histone H1 (95%electrophoretically pure) was purchased from Roche, Indianapolis, Ind.Biotinylated histone H1 was prepared by treating the protein withSulfo-NHS-LC-Biotin from Pierce Rockford, Ill. The biotinylationreaction was conducted by slowly and intermittently adding 3 equivalentsof 10 mM Sulfo-NHS-LC-Biotin to 100 μM Histone H1 in phosphate-bufferedsaline, pH 7.5, at 4° C. with gentle vortexing over 1 min followed bysubsequent 4° C. incubation for 1 hr. Streptavidin coated (FlashPlatePlus) microplates were purchased from Perkin Elmer, Boston, Mass.

PARP1 assay was conducted in PARP assay buffer containing 50 mM Tris pH8.0, 1 mM DTT, 4 mM MgCl₂. PARP reactions contained 1.5 μM [³H]-NAD⁺(1.6 uCi/mmol), 200 nM biotinylated histone H1, 200 nM slDNA, and 1 nMPARP enzyme. Auto reactions utilizing SPA bead-based detection werecarried out in 100 μl volumes in white 96 well plates. Reactions wereinitiated by adding 50 μl of 2×NAD⁺ substrate mixture to 50 μl of 2×enzyme mixture containing PARP and DNA. These reactions were terminatedby the addition of 150 μl of 1.5 mM benzamide (˜1000-fold over itsIC50). 170 μl of the stopped reaction mixtures were transferred tostreptavidin Flash Plates, incubated for 1 hour, and counted using aTopCount microplate scintillation counter. The K_(i) data (nM) weredetermined from inhibition curves at various substrate concentrationsand are shown in Table 1.

TABLE 1 Inhibition of PARP 1.9 12.6 23.7 2.3 13.1 14.5 11.6 3.3 37 5.511.7 2.7 2.8 2.7 15.5 15.6 4.5 10.5 14.6 3.9 8.4 7.2 7.8 10.4 6.1 9.97.7 4.2 8.7 7.5 31.6 5 9.2 2.2 7.4 5.6 12.2 7.9 6.6 9.9 10.8 66 9.4 415.1 6.1 3 7.8 3 65 3.8 68 1.6 2.6 20.5 3.7 13 19.9 12.8 57 19.2 10.616.8 10.6 5.3 2.8 11.4 6.4 5.3 31.5 8.7 8.9 7.2 12.5 7.2 7 1.6 1.6 9.45.2 11.4 20.1 10.4 3.2 2.8 2.1 6.1 2.3 2.8 3 2

Cellular PARP Assay:

C41 cells were treated with a compound of this invention for 30 minutesin 96 well plate. PARP was then activated by damaging DNA with 1 mM H₂O₂for 10 minutes. The cells were then washed with ice-cold PBS once andfixed with pre-chilled methanol:acetone (7:3) at −20° C. for 10 minutes.After air-drying, the plates were rehydrated with PBS and blocked 5%non-fat dry milk in PBS-tween (0.05%) (blocking solution) for 30 minutesat room temperature. The cells were incubated with anti-PAR antibody 10H(1:50) in Blocking solution at 37° C. for 60 minutes followed by washingwith PBS-Tween20 5 times, and incubation with goat anti-mousefluorescein 5(6)-isothiocyanate-coupled antibody (1:50) and 1 μg/ml4′,6-diamidino-2-phenylindole (DAPI) in blocking solution at 37° C. for60 minutes. After washing with PBS-Tween20 5 times, the analysis wasperformed using an fmax Fluorescence Microplate Reader (MolecularDevices, Sunnyvalle, Calif.), set at the excitation wavelength of 490 nmand emission wavelength of 528 nm fluorescein 5(6)-isothiocyanate (FITC)or the excitation wavelength of 355 nm and emission wavelength of 460 nm(DAPI). The PARP activity (FITC signal) was normalized with cell numbers(DAPI).

The cellular assay measures the formation of poly ADP-ribose by PARPwithin cells and demonstrates that compounds of this invention penetratecell membranes and inhibit PARP in intact cells. The EC_(50s) forrepresentative compounds of this invention are provided in Table 2.

TABLE 2 Cellular Activity EC₅₀ (nM) 18 35 3 7.5 1.3 5.2 39 39 3.2 239 218.3 8 20 8.6 26 5.1 174 7.1 5.6 5.9 >1000 86 42 1.9 4.1 7 39 3.3 4.410.7 12 4.3 36 8.4 1.9 3.3 32 15 88 7.7 37 19 108 40 6.7 14 5.2 22 114.2 139 2.3 8.3 5.7 52 26 57 15.8 45 5 5.1 12.4 2.1 5.2 27 12.6 1.7 5.737 3.6 8.4 6.8 6.7 10.1 18.5 5.4 2.3 3.5 0.4 2 1.2 7 1.3 13 1.1 0.3

As PARP inhibitors, the compounds of this invention have numeroustherapeutic applications related to, ischemia reperfusion injury,inflammatory diseases, degenerative diseases, protection from adverseeffects of cytotoxic compounds, and potentiation of cytotoxic cancertherapy. In particular, compounds of this invention potentiate radiationand chemotherapy by increasing cell death of cancer cells, limitingtumor growth, decreasing metastasis, and prolonging the survival oftumor-bearing mammals. Compounds of Formula (I) can treat leukemia,colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of thebreast, and cervical carcinomas.

Other therapeutic applications include, but are not limited to,retroviral infection, arthritis, gout, inflammatory bowel disease, CNSinflammation, multiple sclerosis, allergic encephalitis, sepsis, septicshock, hemmorhagic shock, pulmonary fibrosis, uveitis, diabetes,Parkinsons disease, myocardial infarction, stroke, other neural trauma,organ transplantation, reperfusion of the eye, reperfusion of thekidney, reperfusion of the gut, reperfusion of skeletal muscle, livertoxicity following acetominophen overdose, cardiac and kidney toxicitiesfrom doxorubicin and platinum based antineoplastic agents, and skindamage secondary to sulfur mustards. (G. Chen et al. Cancer Chemo.Pharmacol. 22 (1988), 303; C. Thiemermann et al., Proc. Natl. Acad. Sci.USA 94 (1997), 679-683 D. Weltin et al. Int. J. Immunopharmacol. 17(1995), 265-271; H. Kroger et al. Inflammation 20 (1996), 203-215; W.Ehrlich et al. Rheumatol. Int. 15 (1995), 171-172; C. Szabo et al.,Proc. Natl. Acad. Sci. USA 95 (1998), 3867-3872; S. Cuzzocrea et al.Eur. J. Pharmacol. 342 (1998), 67-76; V. Burkhart et al., NatureMedicine (1999), 5314-19).

Determination of In Vivo Efficacy

PARP Inhibitors in Combination with Cisplatin in an Early Staged MX-1Breast Carcinoma Xenograft Model

0.2 cc of 1:10 MX-1 tumor brei, was injected subcutaneously into theflank of female SCID mice (Charles River Labs) on study day 0. On day15, tumors were size matched (188+25 mm³) and the animals were placedinto one of two therapy groups:

Group 1 vehicle (s.c. OMP x7)+Cisplatin 6 mg/kg/day (i.p., qd×1)

Group 2 PARP±25 mg/kg/day (s.c. OMP×7)+Cisplatin 6 mg/kg/day (i.p.,qd×1)

The vehicle for both the PARP inhibitor and cisplatin was 0.9% NaCl.There were 8-10 rats in each group. Treatment with the PARPi began onday 16 while cisplatin treatment was started on day 18. At variousintervals following tumor cell inoculation, the individual tumordimensions were serially measured using calibrated microcalipers and thetumor volumes calculated according to the formula V=L×W²/2 (V: volume,L: length, W: width). Mice were humanely euthanized when the tumorvolumes reached a predetermined size.

Table 3 shows the average tumor volume for both treatment groups. ThePARP inhibitor, potentiated cisplatin activity as reflected by theenhanced antitumor activity at Day 48.

TABLE 3 Tumor Dose Volume^(a) Compound (mg/kg/day) (Day 48) Vhl(PARPi)/Cis 0/6 1389 ± 300 PARPi/Cis 25/6   519 ± 104

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of this invention can be employed as azwitterion or as a pharmaceutically acceptable salt. By a“therapeutically effective amount” of the compound of the invention ismeant a sufficient amount of the compound to treat or prevent a diseaseor disorder ameliorated by a PARP inhibitor at a reasonable benefit/riskratio applicable to any medical treatment. It will be understood,however, that the total daily usage of the compounds and compositions ofthis invention will be decided by the attending physician within thescope of sound medical judgment. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed, the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidential with the specificcompound employed; and like factors well known in the medical arts. Forexample, it is well within the skill of the art to start doses of thecompound at levels lower than those required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved.

By “pharmaceutically acceptable salt” is meant those salts which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell-known in the art. The salts can be prepared in situ during thefinal isolation and purification of the compounds of this invention orseparately by reacting the free base of a compound of this inventionwith a suitable acid. Representative acids include, but are not limitedto acetatic, citric, aspartic, benzoic, benzenesulfonic, butyric,fumaric, hydrochloric, hydrobromic, hydroiodic, lactic, maleic,methanesulfonic, pamoic, pectinic, pivalic, propionic, succinic,tartaric, phosphic, glutamic, and p-toluenesulfonic. Also, the basicnitrogen-containing groups can be quaternized with such agents as loweralkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained.

A compound of this invention may be administered as a pharmaceuticalcomposition containing a compound of this invention in combination withone or more pharmaceutically acceptable excipients. A pharmaceuticallyacceptable carrier or excipient refers to a non-toxic solid, semi-solidor liquid filler, diluent, encapsulating material or formulationauxiliary of any type. The compositions can be administeredparenterally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments, drops or transdermal patch),rectally, or bucally. The term “parenteral” as used herein refers tomodes of administration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically-acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol, and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity may be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorption,such as aluminum monostearate and gelatin.

Compounds of this invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically-acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of this invention, stabilizers, preservatives, excipients, andthe like. The preferred lipids are the phospholipids and thephosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Total daily dose of the compositions of the invention to be administeredto a human or other mammal host in single or divided doses may be inamounts, for example, from 0.0001 to 300 mg/kg body weight daily andmore usually 1 to 300 mg/kg body weight. The dose, from 0.0001 to 300mg/kg body, may be given twice a day.

Abbreviations which have been used in the descriptions of the examplesthat follow are: DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DMF forN,N-dimethylformamide; DMSO for dimethylsulfoxide; Et₂O for diethylether; EtOAc for ethyl acetate; EtOH for ethanol; HPLC for high pressureliquid chromatography; LDA for lithium diisopropylamide; MeOH formethanol; psi for pounds per square inch; TFA for trifluoroacetic acid;THF for tetrahydrofuran, and TMS for trimethylsilane.

Compounds having formula I may be made by synthetic chemical processes,examples of which are shown herein below. It is meant to be understoodthat the order of the steps in the processes may be varied, thatreagents, solvents and reaction conditions may be substituted for thosespecifically mentioned, and that vulnerable moieties may be protectedand deprotected, as necessary.

As shown in Scheme 1, compounds having formula 1 may be converted tocompounds having formula 3 by reacting the former, compounds havingformula 2 wherein PG symbolizes a protecting group, and an amide formingreagent, such as 1,1′-carbonyldiimidazole (CDI). Compounds havingformula 3 may be converted to compounds having formula 4 when treatedwith an acid, such as acetic acid, and heat. The protecting group ofcompounds having formula 4 may be removed using hydrogenolysisconditions (for CBZ) or acidic conditions (for BOC) to give compoundshaving formula 5. Compounds having formula 5 may be alkylated underreductive amination conditions with either a ketone or aldehyde to yieldcompounds having formula 6.

As shown in Scheme 2, compounds having formula 1 may be converted tocompounds having formula 8 by reacting the former with compounds havingformula 7, and an amide forming reagent, such as1,1′-carbonyldiimidazole (CDI). Compounds having formula 8 may beconverted to compounds having formula 6 when treated with an acid, suchas acetic acid, and heat.

As shown in Scheme 3, compounds having formula 1 may be converted tocompounds having formula 10 by reacting the former, compounds havingformula 9, and an amide forming reagent, such as1,1′-carbonyldiimidazole (CDI). Compounds having formula 10 may beconverted to compounds having formula 11 when treated with an acid, suchas acetic acid, and heat. Compounds having formula 11 may be reducedwith hydrogen and a catalyst such as palladium to form compounds havingformula 12. Compounds having formula 12 may be alkylated under reductiveamination conditions using either a ketone or aldehyde to yieldcompounds having formula 13.

As shown in Scheme 4, compounds having formula 1 may be converted tocompounds having formula 15 by reacting the former, compounds havingformula 14 wherein X is halogen, and an amide forming reagent, such as1,1′-carbonyldiimidazole (CDI). Compounds having formula 15 may beconverted to compounds having formula 16 when treated with an acid, suchas acetic acid, and heat. Compounds having formula 16 may be convertedto compounds having formula 22 by reacting the former and compoundshaving formula 21 under standard palladium-catalyzed conditions.Compounds having formula 22 may be reduced with hydrogen and a catalystsuch as palladium to yield compounds having formula 23 which may bealkylated under reductive amination conditions using either a ketone oraldehyde to provide compounds having formula 24.

Additionally compounds having formula 16 may be converted to compoundshaving formula 18 by treating the former with compounds having formula17 under standard palladium-catalyzed conditions. Compounds havingformula 18 may be reduced to provide compounds having formula 19 whichmay be alkylated under reductive amination conditions using either aketone or aldehyde to provide compounds having formula 20.

The following Examples are intended as an illustration of and not alimitation upon the scope of the invention as defined in the attachedclaims. The compounds of this invention can be prepared by a variety ofsynthetic routes.

Example 1 2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamideExample 1A tert-butyl4-(4-(2-amino-3-carbamoylphenylcarbamoyl)phenyl)piperidine-1-carboxylate

A solution of tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate (1g) in pyridine (3 mL) and DMF (3 mL) at 40° C. was stirred for 30minutes, treated with carbonyl diimidazole (CDI, 0.55 g), stirred for 1hour, treated with 2,3-diaminobenzamide dihydrochloride (synthesized asdescribed in U.S. Pat. No. 6,737,421, 0.73 g), stirred for 1 hour atambient temperature, treated with isopropanol, (10 mL), cooled for 18hours at 0° C. and filtered. The filtrant was dissolved in water (10mL), treated with 50% aqueous NaOH (0.26 mL), stirred for 3 hours atambient temperature and filtered.

Example 1B 2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 1A (0.175 g) in acetic acid (2 mL) at reflux wasstirred for 90 minutes and concentrated. The concentrate was dissolvedin water, treated with 50% aqueous NaOH (0.2 mL) and filtered. Thefiltrate was concentrated and purified by high performance liquidchromatography (HPLC) on a C18 column with 0-100% CH₃CN/water/0.1%trifluoroacetic acid (TFA). ¹H NMR (DMSO-d₆) δ 9.25 (s, 1H), 8.61 (s,1H), 8.34 (s, 1H), 8.22 (d, J=8.42 Hz, 1H), 7.87 (d, J=6.55 Hz, 1H),7.74 (d, J=7.18 Hz, 2H), 7.46 (d, J=8.11 Hz, 2H), 7.35 (t, J=7.80 Hz,1H), 3.42 (d, J=12.48 Hz, 2H), 3.01-3.09 (m, 2H), 2.97 (ddd, J=12.01,8.58, 3.43 Hz, 1H), 2.00 (s, 2H), 1.84 (qd, J=13.05, 3.90 Hz, 2H).

Example 2 2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamideExample 2A 2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

A mixture of 2,3-diaminobenzamide dihydrochloride (1 g),4-pyridin-2-ylbenzaldehyde (0.82 g) and 10% Pd/C (0.3 g) in methanol (30mL) at reflux was stirred for 18 hours, cooled, filtered throughdiatomaceous earth (Celite®) and concentrated. The concentrate wascrystallized from methanol.

Example 2B 2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

A mixture of EXAMPLE 2A (0.905 g) and PtO₂ in acetic acid (20 mL) atambient temperature under hydrogen (60 psi) was stirred for 4.5 hours,filtered through a nylon membrane and concentrated. The concentrate waspurified by chromatography on silica gel with 10%methanol/dichloromethane. ¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.33 (d,J=8.11 Hz, 2H), 7.89 (d, J=7.49 Hz 1H), 7.73-7.81 (m, 4H), 7.36 (t,J=7.64 Hz, 1H), 4.27 (dd, J=11.70, 2.96 Hz, 1H), 3.17 (s, 1H), 3.03 (td,J=12.24, 4.21 Hz, 2H), 1.81-1.97 (m, 6H), 1.63-1.66 (m, 1H).

Example 32-(4-(1-methyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 2 (0.05 g) and 36% formaldehyde in water (0.012mL) in methanol (1 mL) was treated with sodium cyanoborohydride (0.01 g)and acetic acid (0.2 mL), stirred for 18 hours and concentrated. Theconcentrate was purified by chromatography on silica gel with 10%methanol/dichloromethane. ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.15-8.24 (m,2H), 7.87 (d, J=7.49 Hz 1H), 7.72 (d, J=6.86 Hz, 2H), 7.53 (d, J=7.80Hz, 2H), 7.32-7.39 (m, 1H), 2.99 (s, 1H), 2.82 (s, 1H), 1.91 (s, 5H),1.79 (d, J=14.66 Hz, 2H), 1.67 (s, 3H), 1.31-1.48 (m, 1H).

Example 42-(4-(1-ethylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting acetaldehyde for formaldehydein EXAMPLE 3. ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.32 (s, 1H), 8.15 (s,1H), 7.82-7.92 (m, 3H), 7.75 (d, J=7.93 Hz, 2H), 7.36 (t, J=7.63 Hz,1H), 4.10 (q, J=5.19 Hz, 1H), 3.17 (d, J=5.19 Hz, 2H), 2.09 (s, 1H),2.04 (s, 1H), 1.78-1.91 (s, 5H), 1.19 (s, 1H), 1.06-1.15 (m, 2H),0.87-0.95 (m, 1H).

Example 52-(4-(1-isopropyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting acetone for formaldehyde inEXAMPLE 3. ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.17 (m, 2H), 7.86 (d,J=7.67 Hz 1H), 7.73 (s, 3H), 7.52 (s, 1H), 7.33 (m, 1H), 2.93 (s, 1H),2.16 (s, 1H), 1.73 (s, 3H), 1.48 (s, 2H), 1.26 (d, J=6.14 Hz, 2H), 1.11(m, 1H), 0.95 (s, 2H), 0.76 (s, 2H).

Example 6 2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamideExample 6A 2-(4-pipiridin-3-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting pyridin-3-yl-benzoic acid fortert-butyl 4-(4-carboxy-phenyl)-piperidine-1-carboxylate in EXAMPLE 1.

Example 6B 2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting EXAMPLE 6A for EXAMPLE 2A inEXAMPLE 2. ¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.16 (d, J=7.93 Hz, 1H),7.85 (d, J=7.63 Hz 1H), 7.73 (d, J=8.24 Hz, 2H), 7.45 (d, J=8.24 Hz,2H), 7.32 (t, J=7.78 Hz, 1H), 3.03 (d, J=11.29 Hz, 1H), 2.97 (d, J=12.21Hz, 1H), 2.67-2.75 (m, 1H), 2.52-2.62 (m, 2H), 1.91 (s, 1H), 1.66-1.71(m, 1H), 1.63 (dd, J=12.21, 3.05 Hz, 1H), 1.52 (d, J=12.21 Hz, 1H).

Example 72-(4-(1-isopropyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting EXAMPLE 6 for EXAMPLE 2 inEXAMPLE 5. ¹H NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.21 (d, J=8.29 Hz, 2H),7.87 (d, J=7.36 Hz 1H), 7.73 (d, J=7.67 Hz, 2H), 7.55 (d, J=8.29 Hz,2H), 7.34 (t, J=7.83 Hz, 1H), 3.43 (m, 4H), 3.16 (d, J=5.22 Hz, 2H),2.98 (m, 1H) 1.90-2.07 (m, 2H), 1.79-1.89 (m, 1H), 1.27 (d, J=4.60 Hz,6H).

Example 82-(4-(1-methyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting EXAMPLE 6 for EXAMPLE 2 inEXAMPLE 3. ¹H NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.15 (d, J=7.98 Hz, 2H),7.85 (d, J=7.36 Hz 1H), 7.71 (d, J=7.06 Hz, 2H), 7.48 (t, J=7.83 Hz,2H), 7.32 (t, J=7.83 Hz, 1H), 2.77-2.88 (m, 3H), 2.20 (s, 3H), 1.95-2.03(m, 1H), 1.88-1.05 (m, 1H), 1.85 (s, 2H), 1.67-1.75 (m, 1H), 1.56-1.67(m, 1H), 1.43 (dd, J=11.97, 3.99 Hz, 1H).

Example 92-(4-(1-ethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting EXAMPLE 6 for EXAMPLE 2 inEXAMPLE 4. ¹H NMR (DMSO-d₆) δ 9.48 (s, 1H), 8.28 (d, J=8.29 Hz, 2H),7.98 (d, J=7.36 Hz 1H), 7.84 (d, J=7.36 Hz, 2H), 7.60 (d, J=7.98 Hz,2H), 7.45 (t, J=7.67 Hz, 1H), 3.00-3.08 (m, 2H), 2.92-2.98 (m, 1H), 2.50(q, J=7.26 Hz, 2H), 2.13 (t, J=10.74 Hz, 1H), 2.04 (d, J=11.97 Hz, 1H),1.97 (s, 2H), 1.82-1.90 (m, 1H), 1.67-1.78 (m, 1H), 1.61 (td, J=12.04,3.53 Hz, 1H), 1.13 (t, J=7.21 Hz, 3H).

Example 102-(4-(1-benzyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting benzaldehyde for formaldehydein EXAMPLE 8. ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.13 (d, J=7.98 Hz, 2H),7.93 (d, J=7.06 Hz 1H), 7.85 (d, J=7.36 Hz, 1H), 7.70 (d, J=7.36 Hz,2H), 7.41-7.50 (m, 3H), 7.29-7.34 (m, 5H), 3.51 (s, 2H), 2.86 (m, 4H),2.00-2.10 (m, 2H), 1.80 (s, 1H), 1.69-1.75 (m, 1H), 1.60-1.68 (m, 1H),1.48-1.58 (m, 1H).

Example 112-(4-(1-phenethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting phenylacetaldehyde forformaldehyde in EXAMPLE 8. ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.14 (d,J=7.98 Hz, 2H), 7.85 (d, J=7.67 Hz 1H), 7.71 (d, J=7.06 Hz, 2H), 7.48(d, J=8.29 Hz, 2H), 7.33 (t, J=7.67 Hz, 1H), 7.14-7.28 (m, 5H), 2.92-3.0(m, 3H), 2.82-2.86 (m, 2H), 2.69-2.81 (m, 3H), 2.03-2.14 (m, 2H),1.70-1.90 (m, 2H), 1.55-1.65 (m, 1H), 1.44-1.54 (m, 1H).

Example 12 benzyl4-(3-(4-(4-carbamoyl-1H-benzimidazol-2-yl)phenyl)piperidin-1-ylmethyl)-1-carboxylate

This compound was prepared by substituting benzyl4-formylpiperidine-1-carboxylate for formaldehyde in EXAMPLE 8. ¹H NMR(DMSO-d₆) δ 9.36 (s, 1H), 8.15 (d, J=7.98 Hz, 2H), 7.86 (d, J=7.36 Hz1H), 7.66-7.75 (m, 2H), 7.49 (d, J=8.29 Hz, 2H), 7.29-7.39 (m, 6H), 5.06(s, 2H), 3.98 (s, 2H), 2.83 (s, 5H), 2.17 (d, J=6.75 Hz, 2H), 1.86-2.04(m, 2H), 1.73 (d, J=9.82 Hz, 5H), 1.55-1.65 (m, 1H), 1.44-1.54 (m, 1H),0.90-1.05 (m, 2H).

Example 132-(4-(1-(4-morpholin-4-yl-benzyl)piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting 4-morpholin-4-yl-benzaldehydefor formaldehyde in EXAMPLE 8. ¹H NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.14 (d,J=8.42 Hz, 2H), 7.85 (d, J=7.49 Hz 1H), 7.72 (d, J=8.11 Hz, 2H), 7.45(d, J=8.42 Hz, 2H), 7.33 (t, J=7.80 Hz, 1H), 7.15 (d, J=8.42 Hz, 1H),6.88 (d, J=8.73 Hz, 1H), 3.69-3.74 (m, 4H), 3.05-3.09 (m, 4H), 2.81-2.88(m, 4H), 1.97-2.06 (m, 2H), 1.72 (dt, J=6.55, 3.28 Hz, 1H), 1.56-1.65(m, 2H), 1.49 (td, J=11.93, 3.90 Hz, 1H).

Example 142-(4-(1-(4-piperidin-1-ylbenzyl)piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting 4-piperidin-1-yl-benzaldehydefor acetaldehyde in EXAMPLE 8. ¹H NMR (DMSO-d₆) δ 9.30 (s, 1H), 8.14 (d,J=8.42 Hz, 2H), 7.85 (d, J=7.49 Hz 1H), 7.68-7.74 (m, 2H), 7.45 (d,J=8.42 Hz, 2H), 7.32 (t, J=7.64 Hz, 1H), 7.12 (d, J=8.42 Hz, 2H), 6.85(d, J=8.73 Hz, 2H), 3.22 (m, 2H), 3.07 (m, 2H), 2.84 (d, J=13.41 Hz,3H), 1.97-2.01 (m, 1H), 1.74 (m, 1H), 1.55-1.64 (m, 5H), 1.46-1.55 (m,3H), 1.22-1.26 (m, 1H).

Example 152-(4-(1-piperidin-4-ylmethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

A mixture of EXAMPLE 12 (0.057 g) and 20% Pd(OH)₂/C (0.01 g) in ethanol(5 mL) and acetic acid (0.5 mL), was stirred under hydrogen for 18hours, filtered and concentrated. The concentrate was purified bychromatography on silica gel with 10% methanol/dichloromethane. ¹H NMR(DMSO-d₆) δ 9.33 (s, 1H), 8.16 (d, J=8.29 Hz, 2H), 7.84 (d, J=7.67 Hz2H), 7.72 (d, J=7.98 Hz, 2H), 7.48 (d, J=8.29 Hz, 2H), 7.31 (t, J=7.67Hz, 1H), 3.17 (s, 2H), 2.89-2.94 (m, 3H), 2.83-2.88 (m, 3H), 2.46 (s,1H), 2.14 (d, J=7.06 Hz, 2H), 2.02 (t, J=10.13 Hz, 1H), 1.50-1.73 (m,5H), 1.44-1.54 (m, 1H), 0.95-1.05 (m, 2H).

Example 162-(4-(1-ethyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting EXAMPLE 1 for EXAMPLE 2 inEXAMPLE 4. ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.22 (d, J=8.29 Hz, 2H),7.87 (d, J=7.36 Hz, 2H), 7.77 (d, J=7.67 Hz, 2H), 7.48 (d, J=7.67 Hz,2H), 7.35 (t, J=7.67 Hz, 1H), 3.49-3.59 (m, 2H), 3.14-3.19 (m, 2H),2.90-3.07 (m, 2H), 2.06-2.12 (m, 2H), 1.91 (d, J=5.52 Hz, 3H), 1.27 (t,J=7.21 Hz, 3H), 1.20 (d, J=7.36 Hz, 1H).

Example 17 tert-butyl4-(4-(4-carbamoyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate

A solution of the product of EXAMPLE 1 (0.085 g),di-tert-butyldicarbonate (0.25 g), triethylamine (0.2 mL) and4-dimethylaminopyridine (catalytic), in dichloromethane (2 mL) wasstirred at ambient temperature for 72 hours and concentrated. Theconcentrate was purified by chromatography on silica gel with 7%methanol/dichloromethane. ¹H NMR (DMSO-d₆) δ 8.17 (d, J=8.29 Hz, 2H),7.85 (d, J=7.67 Hz, 1H), 7.72 (d, J=7.98 Hz, 2H), 7.47 (d, J=8.59 Hz,2H), 7.32 (t, J=7.83 Hz, 1H), 4.06-4.12 (m, 2H), 2.74-2.92 (m, 2H),1.75-1.85 (m, 2H), 1.55 (dd, J=12.43, 3.84 Hz, 2H), 1.43 (s, 9H),1.33-1.39 (m, 2H).

Example 182-(4-(1-methyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting EXAMPLE 1 for EXAMPLE 2 inEXAMPLE 3. ¹H NMR (DMSO-d₆) δ 9.35 (d, J=2.75 Hz, 1H), 8.22 (d, J=8.24Hz, 2H), 7.87 (d, J=7.32 Hz, 1H), 7.73-7.80 (m, 2H), 7.48 (d, J=7.93 Hz,2H), 7.35 (t, J=7.78 Hz, 1H), 3.51 (s, 2H), 3.11 (s, 1H), 2.94 (s, 1H),2.83 (s, 3H), 2.05 (s, 2H), 1.91 (s, 2H), 1.23 (s, 1H).

Example 192-(4-(1-isopropyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting EXAMPLE 1 for EXAMPLE 2 inEXAMPLE 5. ¹H NMR (DMSO-d₆) δ 8.97 (s, 1H), 8.23 (d, J=8.24 Hz, 2H),7.87 (d, J=7.63 Hz, 1H), 7.73-7.81 (m, 2H), 7.47 (d, J=8.24 Hz, 2H),7.36 (t, J=7.78 Hz, 1H), 3.53 (d, J=9.46 Hz, 1H), 3.26 (s, 1H),3.10-3.16 (m, 3H), 3.00 (ddd, J=12.13, 8.77, 3.81 Hz, 1H), 2.11 (d,J=13.73 Hz, 2H), 1.91-2.00 (m, 2H), 1.30 (d, J=6.71 Hz, 6H).

Example 202-(4-piperidin-4-ylmethylphenyl)-1H-benzimidazole-4-carboxamide Example20A tert-butyl4-(4-(2-amino-3-carbamoylphenylcarbamoyl)benzyl)piperidine-1-carboxylate

A solution of (4-(N-Boc-piperidinyl)methyl)-4-benzoic acid (1.1 g) inpyridine (25 mL) and DMF (25 mL) at 40° C. was treated with CDI (587 mg)over 30 minutes then with 2,3-diaminobenzamide dihydrochloride (772 mg),stirred at ambient temperature for 18 hours and concentrated. Theconcentrate was partitioned between ethyl acetate and dilute aqueoussodium bicarbonate. The solid that precipitated from the bi-phasemixture was collected by filtration, washed with water and ethylacetate, and dried.

Example 20B2-(4-piperidin-4-ylmethylphenyl)-1H-benzimidazole-4-carboxamide

A suspension of EXAMPLE 20A in acetic acid at reflux was stirred for 2hours, cooled and concentrated. The concentrate was dissolved in ethylacetate, washed with sodium bicarbonate and water and concentrated. Theconcentrate was flash chromatographed on silica gel with 20%Methanol/ethyl acetate. ¹H NMR (DMSO-d₆) δ 1.27-1.44 (m, 2H), 1.75 (d,J=13.20 Hz, 2H), 1.82-1.97 (m, 1H), 2.65 (d, J=7.06 Hz, 2H), 2.76-2.92(m, 2H), 3.26 (d, J=12.89 Hz, 2H), 7.35 (t, J=7.83 Hz, 1H), 7.42 (d,J=8.29 Hz, 2H), 7.74 (d, J=0.92 Hz, 1H), 7.76 (d, J=0.92 Hz, 1H), 7.87(d, J=6.75 Hz, 1H), 8.18 (d, J=8.29 Hz, 2H), 8.25 (d, J=7.98 Hz, 1H),8.55 (d, J=11.97 Hz, 1H), 9.26 (s, 1H).

Example 21 tert-butyl2-(4-(4-carbamoyl-1H-benzimidazol-2-yl)phenyl)pyrrolidine-1-carboxylate

N-Boc-4-pyrrolidin-2-ylbenzoic acid (0.29 g) in dimethylformamide (DMF,1 mL) and pyridine (1 mL) at 40° C. was stirred for 10 minutes, treatedwith CDI (0.17 g) stirred for 30 minutes, treated with2,3-diaminobenzamide dihydrochloride (0.22 g), stirred at ambienttemperature for 3.5 hours, treated with isopropanol (2 mL), stirred atambient temperature for 16 hours, treated with isopropanol (5 mL) andhexanes (40 mL) and decanted. The residue was stirred in water (3 mL) atambient temperature with 2 drops 50% NaOH for 5 hours and filtered. Thefiltrant was stirred in acetic acid (3 mL) at reflux for 7.5 hours,cooled and concentrated. The concentrate was stirred in dichloromethane(5 mL) and hexane (15 mL) and filtered. ¹H NMR (DMSO-d₆) δ 13.35 (br,1H), 9.35 (br, 1H), 8.18 (br d, J=7.8 Hz, 2H), 7.87 (d, J=7.4 Hz, 1H),7.75 (br, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.40 (br d, J=8.5 Hz, 2H), 7.34(t, J=7.8 Hz, 1H), 4.79 (br m, 1H), 3.55 (m, 2H), 2.36 (m, 1H), 1.80 (m,3H), 1.41 (s, 4H), 1.12 (s, 5H).

Example 222-(4-(2-Piperidin-2-yl-ethyl)phenyl)-1H-benzimidazole-4-carboxamideExample 22A 2-(4-bromo-2-chlorophenyl)-1H-benzimidazole-4-carboxamide

To 4-bromo-2-chlorobenzoic acid (2.48 g) in pyridine (12 mL) and DMF (12mL) was added CDI (1.88 g). The solution was stirred at 45° C. for 2hours, cooled, treated with 2,3-diaminobenzamide dihydrochloride (2.36g), stirred at ambient temperature for 18 hours, and concentrated. Theconcentrate was partitioned between ethyl acetate (70 mL) and water (100mL) and filtered. The filtrant was washed with water and ethyl acetateand dried. This solid was suspended in acetic acid (40 mL) and themixture was heated at 125° C. for 4 hours and filtered. The filtrate wascooled to ambient temperature and filtered. The filtrant was washed withmethanol and dried to give the first batch of product. The mother liquorwas concentrated and the concentrate was treated with dichloromethaneand filtered to provide a second batch of solid.

Example 22B2-(2-chloro-4-(2-pyridin-2-yl-vinyl)phenyl)-1H-benzimidazole-4-carboxamide

To EXAMPLE 22A (200 mg), Pd₂(dba)₃ (palladium dibenzylideneacetone, 52mg) and tri-o-tolylphosphine (52 mg) was added DMF (10 mL),2-vinylpyridine (123 μL) and triethylamine (238 μL). The mixture waspurged with nitrogen and stirred at 80° C. for 18 hours, cooled toambient temperature, filtered through a membrane filter andconcentrated. The concentrate was purified by HPLC (Zorbax, C-18,250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA inCH₃CN; 0-100% gradient).

Example 22C2-(4-(2-pyridin-2-yl-ethyl)phenyl)-1H-benzimidazole-4-carboxamide

To EXAMPLE 22B (100 mg) in a mixture of methanol (10 mL) anddichloromethane (4 mL) was added 10% Pd/C (30 mg) under nitrogen. Thissuspension was purged with hydrogen and was stirred under hydrogen(balloon) for 4 hours. Solid material was filtered off and the filtratewas concentrated. The concentrate was purified by HPLC (Zorbax, SB C-18,250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA inCH₃CN; 0-100% gradient).

Example 22D2-(4-(2-piperidin-2-yl-ethyl)phenyl)-1H-benzimidazole-4-carboxamide

To EXAMPLE 22C (30 mg) in methanol (20 mL) was added of Pd(OH)₂/C (50mg). The reaction mixture was purged with hydrogen, shaken under 60 psiof hydrogen for 18 hours, and filtered. The filtrate was concentrated,and the concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column,mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH₃CN; 0-100%gradient). ¹H NMR (CD₃OD) δ 1.47-1.62 (m, 3H), 1.66-1.72 (m, 1H),1.88-1.98 (m, 3H), 1.99-2.07 (m, 1H), 2.14 (d, J=15.26 Hz, 1H),2.81-2.95 (m, 2H), 3.01 (t, J=12.82 Hz, 1H), 3.11-3.19 (m, 1H),3.37-3.44 (m, 1H), 7.56 (d, J=7.93 Hz, 2H), 7.57 (t, J=7.78 Hz, 1H),7.90 (d, J=7.32 Hz, 1H), 8.01 (d, J=7.63 Hz, 1H), 8.15 (d, J=8.54 Hz,1H).

Example 232-(4-(1-isopropylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

To EXAMPLE 38 (100 mg) in methanol (10 mL) was added acetone (38 mg).The solution was stirred at ambient temperature for 40 minutes, treatedwith sodium triacetoxyborohydride (253 mg) and acetic acid (100 μL),stirred for 18 hours, treated with dichloromethane and washed withdilute NaOH and water. The organic phase was concentrated and theconcentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobilephase A: 0.1% TFA in water; B: 0.1% TFA in CH₃CN; 0-100% gradient). ¹HNMR (CD₃OD) δ 1.44 (d, J=6.71 Hz, 6H), 2.16-2.34 (m, 1H), 2.56-2.63 (m,1H), 3.24-3.37 (m, 1H), 3.52-3.61 (m, 2H), 3.64-3.73 (m, 1H), 3.77-3.88(m, 2H), 4.02 (dd, J=10.68, 7.02 Hz, 1H), 7.54 (t, J=7.93 Hz, 1H), 7.65(d, J=7.93 Hz, 2H), 7.88 (d, J=7.63 Hz, 1H), 7.99 (d, J=7.63 Hz, 1H),8.19 (d, J=7.93 Hz, 2H).

Example 242-(4-(1-cyclopentylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting cyclopentanone for acetone. ¹H NMR (CD₃OD) δ 1.68-1.91 (m,6H), 2.15-2.25 (m, 2H), 2.28-2.37 (m, 1H), 2.55-2.63 (m, 1H), 3.26-3.33(m, 1H), 3.49-3.55 (m, 1H), 3.67-3.77 (m, 2H), 3.82-3.94 (m, 2H), 4.06(dd, J=10.68, 7.02 Hz, 1H), 7.53 (t, J=7.78 Hz, 1H), 7.64 (d, J=7.63 Hz,2H), 7.88 (d, J=7.32 Hz, 1H), 7.99 (d, J=7.63 Hz, 1H), 8.18 (d, J=7.93Hz, 2H).

Example 252-(4-(1-cyclohexylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting cyclohexanone for acetone. ¹H NMR (CD₃OD) δ 1.16-1.36 (m,3H), 1.41-1.52 (m, 2H), 1.66 (d, J=12.82 Hz, 1H), 1.79-1.92 (m, 2H),2.01 (d, J=12.21 Hz, 1H), 2.09-2.15 (m, J=11.60 Hz, 1H), 2.23-2.35 (m,3H), 2.55-2.63 (m, 1H), 3.12-3.20 (m, 1H), 3.49-3.56 (m, 1H), 3.69-3.77(m, 1H), 4.80 (t, J=7.93 Hz, 1H), 7.47 (t, J=7.93 Hz, 1H), 7.80 (d,J=8.24 Hz, 2H), 7.84 (d, J=7.63 Hz, 1H), 7.99 (d, J=7.63 Hz, 1H), 8.33(d, J=8.24 Hz, 2H).

Example 262-(2-fluoro-4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamideExample 26A 2-(4-bromo-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

4-Bromo-2-fluorobenzoic acid (5 g) in a mixture of pyridine (50 mL) andDMF (50 mL) at 45° C. was treated with CDI (0.856 g), stirred at 45° C.for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (5.1 g),stirred at ambient temperature for 18 hours and concentrated. Theconcentrate was dissolved in acetic acid (100 mL), heated at 70° C. for1 hour and concentrated. The concentrate was partitioned between ethylacetate and sodium bicarbonate solution and the organic phase wasisolated, washed with brine and concentrated. The concentrate was flashchromatographed on silica gel with ethyl acetate.

Example 26B2-(2-fluoro-4-pyridin-4-ylphenyl)-1H-benzimidazole-4-carboxamide

To EXAMPLE 26A (200 mg), Pd₂(dba)₃ (55 mg) and tri-o-tolylphosphine (55mg) was added DMF (10 mL), 4-(tri-n-butylstannyl)pyridine (220 mg) andtriethylamine (238 μL). The mixture was purged with nitrogen, heated at75° C. for 18 hours, cooled and flash chromatographed on silica gel with(5% Methanol/20% ethyl acetate/75% hexanes). Product was recrystallizedfrom methanol.

Example 26C2-(2-fluoro-4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide

Example 26B (80 mg) and catalytic 5% Pt/C in methanol (10 mL) washydrogenated under 60 psi of hydrogen until starting material wasconsumed and filtered. The filtrate was concentrated and the concentratepurified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1%TFA in water; B: 0.1% TFA in CH₃CN; 0-100% gradient). ¹H NMR (CD₃OD) δ1.93-2.02 (m, 2H), 2.15 (d, J=14.04 Hz, 2H), 3.03-3.10 (m, 1H),3.14-3.22 (m, 2H), 3.55 (d, J=12.82 Hz, 2H), 7.32-7.40 (m, 2H), 7.52 (t,J=7.93 Hz, 1H), 7.90 (d, J=7.93 Hz, 1H), 8.01 (d, J=7.63 Hz, 1H), 8.21(t, J=7.78 Hz, 1H).

Example 272-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 26 andsubstituting 3-(tri-n-butylstannyl)pyridine for4-(tri-n-butylstannyl)pyridine. ¹H NMR (CD₃OD) δ 1.83-1.97 (m, 2H),2.07-2.13 (m, 2H), 3.04-3.10 (m, 1H), 3.14-3.21 (m, 2H), 3.45-3.55 (m,2H), 7.38-7.41 (m, 2H), 7.50 (t, J=7.78 Hz, 1H), 7.88 (d, J=7.93 Hz,1H), 8.00 (d, J=7.63 Hz, 1H), 8.22 (t, J=8.09 Hz, 1H).

Example 282-(4-(1-isopropylpiperidin-4-ylmethyl)phenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 19 (50 mg) in acetone and 1,2-dichloroethane (5mL) was stirred for 40 minutes, treated with sodiumtriacetoxyborohydride (63 mg) and acetic acid (43 μL), stirred for 18hours and concentrated. The concentrate was purified by HPLC (ZorbaxC-8, 0.1% TFA/CH₃CN/water). ¹H NMR (CD₃OD) δ 1.34 (d, J=6.75 Hz, 6H),1.52-1.61 (m, 2H), 1.97-2.00 (m, 3H), 2.76 (d, J=6.44 Hz, 2H), 3.00 (t,J=11.97 Hz, 2H), 3.40-3.54 (m, 3H), 7.46-7.56 (m, 3H), 7.86 (d, J=7.98Hz, 1H), 7.99 (d, J=7.67 Hz, 1H), 8.14 (d, J=8.29 Hz, 2H).

Example 292-(4-(1-isopropylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 33 for EXAMPLE 38. ¹H NMR (CD₃OD) δ 1.34 (dd,J=6.56, 1.98 Hz, 6H), 2.23-2.37 (m, 3H), 2.56-2.64 (m, 1H), 3.45-3.56(m, 2H), 3.66-3.74 (m, 1H), 4.71-4.77 (m, 1H), 7.49 (t, J=7.93 Hz, 1H),7.81-7.86 (m, 3H), 7.99 (d, J=7.63 Hz, 1H), 8.32 (d, J=8.54 Hz, 2H).

Example 302-(4-(1-cyclopropylmethylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting cyclopropylcarboxaldehyde for acetone. ¹H NMR (CD₃OD) δ0.46-0.51 (m, 2H), 0.74-0.79 (m, 2H), 1.16-1.24 (m, 1H), 2.18-2.38 (m,1H), 2.56-2.65 (m, 1H), 3.17-3.38 (m, 2H), 3.46-3.54 (m, 1H), 3.71-3.78(m, 1H), 3.85-3.94 (m, 1H), 3.95-4.02 (m, 1H), 4.09-4.14 (m, 1H), 7.54(t, J=7.93 Hz, 1H), 7.65 (d, J=8.24 Hz, 2H), 7.88 (d, J=7.63 Hz, 1H),7.99 (d, J=7.63 Hz, 1H), 8.19 (d, J=7.93 Hz, 2H).

Example 312-(4-(1-cyclopentylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 24 andsubstituting EXAMPLE 33 for EXAMPLE 38. ¹H NMR (CD₃OD) δ 1.33-1.43 (m,1H), 1.54-1.91 (m, 6H), 2.14-2.19 (m, 1H), 2.28-2.37 (m, 3H), 2.59-2.66(m, 1H), 3.46-3.52 (m, 1H), 3.67-3.74 (m, 1H), 3.81-3.87 (m, 1H), 4.68(t, J=7.93 Hz, 1H), 7.48 (t, J=7.93 Hz, 1H), 7.81 (d, J=8.24 Hz, 2H),7.85 (d, J=8.24 Hz, 1H), 8.00 (d, J=7.63 Hz, 1H), 8.32 (d, J=8.24 Hz,2H).

Example 322-(4-(1-cyclohexylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 25 andsubstituting EXAMPLE 33 for EXAMPLE 38. ¹H NMR (CD₃OD) δ 1.16-1.36 (m,3H), 1.41-1.52 (m, 2H), 1.66 (d, J=12.82 Hz, 1H), 1.83 (dd, J=13.12,1.83 Hz, 1H), 1.90 (d, J=13.12 Hz, 1H), 2.01 (d, J=12.21 Hz, 1H), 2.12(d, J=11.60 Hz, 1H), 2.24-2.35 (m, 3H), 2.55-2.63 (m, 1H), 3.12-3.20 (m,1H), 3.48-3.55 (m, 1H), 3.70-3.77 (m, 1H), 4.80 (t, J=7.93 Hz, 1H), 7.47(t, J=7.93 Hz, 1H), 7.80 (d, J=8.24 Hz, 2H), 7.84 (d, J=7.63 Hz, 1H),7.99 (d, J=7.63 Hz, 1H), 8.33 (d, J=8.24 Hz, 2H).

Example 33 2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

Example 21 (0.23 g) in 1M HCl in ethanol (5 mL) was stirred for 19hours, treated with 12M HCl (0.5 mL), stirred for 19 hours, treated with12M HCl (0.5 mL), stirred for 6 hours and concentrated. The concentratewas flash chromatographed on silica gel using 95:5:1 to 80:20:1dichloromethane/methanol/NH₄OH. ¹H NMR (DMSO-d₆) δ 9.34 (br, 1H), 8.17(d, J=8.4 Hz, 2H), 7.85 (d, J=7.4 Hz, 1H), 7.74 (br, 1H), 7.73 (d, J=7.1Hz, 1H), 7.59 (d, J=7.8 Hz, 2H), 7.33 (t, J=7.8 Hz, 1H), 4.18 (t, J=7.6Hz, 1H), 3.01 (m, 2H), 2.20 (m, 1H), 1.80 (m, 2H), 1.56 (m, 1H).

Example 342-(4-(1-propylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting propionaldehyde for acetone. ¹H NMR (CD₃OD) δ 1.06 (t,J=7.48 Hz, 3H), 1.77-1.86 (m, 2H), 2.17-2.38 (m, 1H), 2.55-2.64 (m, 1H),3.24-3.34 (m, 2H), 3.42-3.50 (m, 1H), 3.67-3.75 (m, 2H), 3.83-3.95 (m,1H), 4.06 (dd, J=10.37, 7.32 Hz, 1H), 7.51 (t, J=7.78 Hz, 1H), 7.64 (d,J=7.02 Hz, 2H), 7.86 (d, J=7.63 Hz, 1H), 7.99 (d, J=7.63 Hz, 1H), 8.20(d, J=7.93 Hz, 2H).

Example 352-(4-(1-cyclopropylmethylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 30 andsubstituting EXAMPLE 33 for EXAMPLE 38. ¹H NMR (CD₃OD) δ 0.24 (dd,J=8.70, 3.81 Hz, 1H), 0.34-0.41 (m, 1H), 0.63-0.70 (m, 2H), 0.98-1.07(m, 1H), 2.31-2.38 (m, 3H), 2.58-2.66 (m, 1H), 2.98-3.08 (m, 2H),3.42-3.48 (m, 1H), 4.01-4.07 (m, 1H), 4.53-4.60 (m, 1H), 7.46 (t, J=7.78Hz, 1H), 7.78 (d, J=8.24 Hz, 2H), 7.83 (d, J=7.32 Hz, 1H), 7.99 (d,J=6.71 Hz, 1H), 8.32 (d, J=8.24 Hz, 2H).

Example 362-(4-(1-propylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 34 andsubstituting EXAMPLE 33 for EXAMPLE 38. ¹H NMR (CD₃OD) δ 0.93 (t, J=7.32Hz, 3H), 1.58-1.64 (m, 1H), 1.70-1.78 (m, 1H), 2.30-2.39 (m, 3H),2.59-2.64 (m, 1H), 3.03-3.12 (m, 2H), 3.33-3.40 (m, 1H), 3.89-3.95 (m,1H), 4.53-4.58 (m, 1H), 7.43-7.48 (m, 1H), 7.78 (d, J=8.24 Hz, 2H), 7.83(d, J=7.32 Hz, 1H), 7.99 (d, J=7.63 Hz, 1H), 8.33 (d, J=8.54 Hz, 2H).

Example 372-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 26 andsubstituting 2-(tri-n-butylstannyl)pyridine for4-(tri-n-butylstannyl)pyridine. ¹H NMR (CD₃OD) δ 1.77-1.87 (m, 2H),1.97-2.10 (m, 3H), 2.18 (d, J=15.87 Hz, 1H), 3.24 (t, J=10.0, 1H), 3.54(d, J=12.82 Hz, 1H), 4.37-4.42 (m, 1H), 7.44 (t, J=7.93 Hz, 1H),7.51-7.54 (d, J=10.0, 2H), 7.85 (d, J=7.93 Hz, 1H), 7.99 (d, J=7.63 Hz,1H), 8.44 (t, J=7.78 Hz, 1H).

Example 38 3-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared as described in EXAMPLES 21 and 33, usingN-Boc-4-pyrrolidin-3-ylbenzoic acid in place ofN-Boc-4-pyrrolidin-2-ylbenzoic acid. ¹H NMR (DMSO-d₆) δ 9.29 (br, 1H),8.19 (d, J=8.5 Hz, 2H), 7.86 (d, J=7.4 Hz, 1H), 7.75 (br, 1H), 7.73 (d,J=7.9 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.33 (t, J=7.8 Hz, 1H), 3.32-3.46(m, 2H), 3.22 (m, 1H), 3.09 (m, 1H), 2.89 (m, 1H), 2.28 (m, 1H), 1.86(m, 1H).

Example 392-(4-(1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 33 for EXAMPLE 38 and formaldehyde for acetone. ¹HNMR (CD₃OD) δ 2.28-2.45 (m, 3H), 2.58-2.66 (m, 1H), 2.84 (s, 3H),3.31-3.39 (m, 1H), 3.89-3.95 (m, 1H), 4.46-4.52 (m, 1H), 7.44-7.48 (m,1H), 7.78 (d, J=8.24 Hz, 2H), 7.82 (d, J=8.24 Hz, 1H), 7.98 (d, J=7.63Hz, 1H), 8.31 (d, J=8.54 Hz, 2H).

Example 402-(4-(1-methylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting formaldehyde for acetone. ¹H NMR (CD₃OD) δ 2.19-2.39 (m,1H), 2.56-2.65 (m, 1H), 3.06 (s, 3H), 3.23-3.46 (m, 1H), 3.63-3.80 (m,2H), 3.85-4.07 (m, 2H), 7.52 (t, J=7.93 Hz, 1H), 7.62 (d, J=7.93 Hz,2H), 7.86 (d, J=7.93 Hz, 1H), 7.98 (d, J=7.63 Hz, 1H), 8.17 (d, J=8.24Hz, 2H).

Example 412-(2-fluoro-4-(1-isopropylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 27 for EXAMPLE 38. ¹H NMR (CD₃OD) δ 1.41 (d, J=6.41Hz, 3H), 1.42 (d, J=6.41 Hz, 3H), 1.79-2.18 (m, 4H), 3.05-3.13 (m, 1H),3.19-3.33 (m, 2H), 3.52-3.67 (m, 3H), 7.39-7.46 (m, 2H), 7.53 (t, J=7.78Hz, 1H), 7.90 (d, J=8.24 Hz, 1H), 8.01 (d, J=7.63 Hz, 1H), 8.21 (t,J=7.93 Hz, 1H).

Example 422-(4-piperidin-3-yl-3-trifluoromethylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 26 andsubstituting 4-bromo-3-trifluoromethylbenzoic acid for4-bromo-2-fluorobenzoic acid. ¹H NMR (CD₃OD) δ 1.89-2.20 (m, 3H), 2.97(s, 1H), 3.11-3.20 (m, 1H), 3.32-3.66 (m, 4H), 7.44-7.49 (m, 1H), 7.83(d, J=8.24 Hz, 1H), 7.90 (dd, J=11.90, 8.24 Hz, 1H), 7.98 (d, J=7.63 Hz,1H), 8.46 (d, J=8.24 Hz, 1H), 8.54 (s, 1H).

Example 432-(2-fluoro-4-(1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 27 for EXAMPLE 38 and formaldehyde for acetone. ¹HNMR (CD₃OD) δ 1.75-1.83 (m, 1H), 1.93-2.01 (m, 1H), 2.07-2.15 (m, 2H),2.94 (s, 3H), 3.02-3.07 (m, 1H), 3.14-3.22 (m, 2H), 3.30-3.33 (m, 1H),3.58-3.66 (m, 2H), 7.32-7.37 (m, 2H), 7.44 (t, J=7.78 Hz, 1H), 7.84 (d,J=8.24 Hz, 1H), 7.98 (d, J=7.63 Hz, 1H), 8.25-8.29 (m, 1H).

Example 446-chloro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamideExample 44A 2-amino-5-chloro-3-nitrobenzamide

A solution of 2-amino-3-nitrobenzamide (5 g) in acetonitrile (1250 mL)at 60° C. was treated with N-chlorosuccinimide (3.87 g), stirred for 24hours, cooled and filtered.

Example 44B 2,3-diamino-5-chlorobenzamide

To a solution of EXAMPLE 44A (4 g) in THF (500 mL) and ethanol (500 mL)was added 50% Raney nickel in water (2 g). The reaction mixture wasstirred under hydrogen (balloon) for 6 hours and filtered.

Example 44C tert-butyl2-(4-(4-Carbamoyl-6-chloro-1H-benzimidazol-2-yl)phenyl)pyrrolidine-1-carboxylate

A solution of tert-butyl 2-(4-carboxyphenyl)-pyrrolidine-1-carboxylate(500 mg) in dichloromethane (10 mL) was treated with oxalyl chloride(0.15 mL) and DMF (1 drop), stirred for 1 hour and concentrated. Theconcentrate was dissolved in dichloromethane, and this solution wasadded to EXAMPLE 44B (316 mg) in THF (10 mL), treated with triethylamine(2 mL), stirred for 18 hours and concentrated. The concentrate wasdissolved in acetic acid (10 mL), heated at 80° C. for 2 hours andconcentrated. The concentrate was dissolved in ethyl acetate, washedwith sodium bicarbonate solution and brine and concentrated. Theconcentrate was flash chromatographed on silica gel with ethyl acetate.

Example 44D6-chloro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 44C (410 mg) in dichloromethane (20 mL) wastreated with TFA (4 mL), stirred for 1 hour and concentrated. Theconcentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobilephase A: 0.1% TFA in water; B: 0.1% TFA in CH₃CN; 0-100% gradient). ¹HNMR (DMSO-d₆) δ 2.04-2.20 (m, 3H), 2.41-2.52 (m, 2H), 3.33-3.46 (m, 2H),4.65-4.71 (m, 1H), 7.72 (d, J=8.29 Hz, 2H), 7.81-7.84 (m, 1H), 7.95 (s,1H), 8.34 (d, J=8.29 Hz, 2H), 8.94 (s, 1H), 9.14 (s, 1H), 9.73 (s, 1H).

Example 456-Fluoro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamideExample 45A 2-Bromo-4-fluoro-6-nitrophenylamine

To a solution of 4-fluoro-2-nitroaniline (20 g) in a mixture ofdichloromethane (600 mL) and acetic acid (200 mL) was slowly addedbromine (13 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1hour and at ambient temperature for 16 hours. The reaction mixture wasconcentrated and the concentrate partitioned between ethyl acetate (500mL) and sodium bicarbonate solution (500 mL). The organic phase waswashed with sodium bisulphite solution (400 mL) and concentrated. Theconcentrate was recrystallized from hexanes containing somedichloromethane.

Example 45B 2-amino-5-fluoro-3-nitrobenzonitrile

A suspension of EXAMPLE 45A (22.7 g), zinc cyanide (22.6 g) andtetrakis(triphenylphosphine) palladium (7.78 g) in anhydrous DMF (300mL) was heated at 80° C. for 22 hours. After cooling, the reactionmixture was partitioned between ethyl acetate (500 mL) and brine (500mL). The organic phase was washed with water and concentrated.Recrystallization of the concentrate from methanol provided EXAMPLE 45B.

Example 45C 2-amino-5-fluoro-3-nitrobenzamide

A suspension of EXAMPLE 45B (13.9 g) in polyphosphoric acid (400 g) wasstirred at 115° C. for 3 hours. After cooling, water and dichloromethanewere added and the mixture stirred at ambient temperature for 10minutes. The solid material was collected by filtration andrecrystallized from methanol.

Example 45D 2,3-diamino-5-fluorobenzamide

To a solution of EXAMPLE 45C (11.2 g) in a mixture of THF (50 mL) andethanol (50 mL) was added Raney nickel (50% in water, 11.0 g). Themixture was stirred under hydrogen (60 psi) for 5 hours. Solid materialwas filtered off and the filtrate was concentrated.

Example 45E6-fluoro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 44 andsubstituting EXAMPLE 45D for EXAMPLE 44B. ¹H NMR (DMSO-d₆) δ 2.04-2.20(m, 3H), 2.41-2.53 (m, 1H), 3.32-3.49 (m, 2H), 4.69 (s, 1H), 7.60-7.64(m, 2H), 7.72 (d, J=8.24 Hz, 2H), 7.99 (s, 1H), 8.33 (d, J=8.24 Hz, 2H),8.96 (s, 1H), 9.21 (s, 1H), 9.77 (s, 1H).

Example 466-chloro-2-(4-(1-isopropyl-pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 44 for EXAMPLE 38. ¹H NMR (DMSO-d₆) δ 1.23 (d,J=6.41 Hz, 6H), 2.10-2.21 (m, 4H), 2.44-2.49 (m, 1H), 3.35-3.43 (m, 2H),3.58-3.63 (m, 1H), 4.69 (q, J=8.24 Hz, 1H), 7.81-7.85 (m, 3H), 7.98 (s,1H), 8.36 (d, J=8.54 Hz, 2H), 9.14 (s, 1H), 9.78 (s, 1H).

Example 476-chloro-2-(4-(1-cyclopentyl-pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 44 for EXAMPLE 38 and cyclopentanone for acetone.¹H NMR (DMSO-d₆) δ 1.23-1.30 (m, 1H), 1.40-1.50 (m, 2H), 1.55-1.67 (m,2H), 1.70-1.80 (m, 2H), 2.00-2.06 (m, 1H), 2.14-2.21 (m, 4H), 2.47-2.54(m, 1H), 3.39 (dd, J=11.14, 7.17 Hz, 1H), 3.58-3.65 (m, 1H), 3.72-3.78(m, 1H), 4.63 (q, J=8.14 Hz, 1H), 7.80-7.84 (m, 3H), 7.99 (s, 1H), 8.35(d, J=8.54 Hz, 2H), 9.13 (s, 1H), 9.97 (s, 1H).

Example 486-Chloro-2-(4-(1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 44 for EXAMPLE 38 and formaldehyde for acetone. ¹HNMR (DMSO-d₆) δ 2.13-2.27 (m, 3H), 2.48-2.53 (m, 1H), 2.73 (d, J=3.36Hz, 3H), 3.23-3.29 (m, 1H), 3.77-3.82 (m, 1H), 4.44-4.52 (m, 1H), 7.77(d, J=8.54 Hz, 2H), 7.82 (d, J=1.83 Hz, 1H), 7.84 (d, J=1.83 Hz, 1H),7.98 (s, 1H), 8.37 (d, J=8.24 Hz, 2H), 9.12 (s, 1H), 10.09 (s, 1H).

Example 496-fluoro-2-(4-(1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 45 for EXAMPLE 38 and formaldehyde for acetone. ¹HNMR (DMSO-d₆) δ 2.13-2.29 (m, 3H), 2.48-2.54 (m, 1H), 2.73 (s, 3H),3.22-3.31 (m, 1H), 3.77-3.84 (m, 1H), 4.45-4.53 (m, 1H), 7.60-7.65 (m,2H), 7.77 (d, J=8.29 Hz, 2H), 7.96 (s, 1H), 8.35 (d, J=7.98 Hz, 2H),9.19 (s, 1H), 10.19 (s, 1H).

Example 502-(4-(1-ethylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamideExample 50A methyl 4-bromo-2-fluorobenzoate

To a solution of 4-bromo-2-fluorobenzoic acid (30.8 g) in DMF (150 mL)was added iodomethane (17.5 mL) and powdered sodium hydrogencarbonate(23.5 g). The mixture was stirred for 18 hours and partitioned betweenethyl acetate and brine. The organic phase was isolated, washed withdilute sodium bisulfite solution and brine and concentrated. Theconcentrate was flash chromatographed on silica gel with 7-20% ethylacetate/hexanes.

Example 50B tert-butyl2-(3-fluoro-4-methoxycarbonylphenyl)pyrrole-1-carboxylate

A mixture of EXAMPLE 50A (4 g), 1-(tert-butoxycarbonyl)pyrrole-2-boronicacid (5.44 g), and dichlorobis(triphenylphosphine)palladium(II) (1.2 g)in 7:3:2 DME/water/ethanol (300 mL) and 2M aqueous Na₂CO₃ (17.2 mL) at80° C. was stirred for 140 minutes, cooled and concentrated. Theconcentrate was dissolved in ethyl acetate, washed with brine andconcentrated. The concentrate was flash chromatographed on silica gelwith 1:4 ethyl acetate/hexane.

Example 50C tert-butyl2-(3-fluoro-4-methoxycarbonylphenyl)pyrrolidine-1-carboxylate

A mixture of EXAMPLE 50B (5.5 g) and 5% Pt/C (20 mg) in acetic acid (200mL) was hydrogenated at 60 psi for 12 hours and filtered. The filtratewas concentrated and the concentrate partitioned between ethyl acetateand sodium bicarbonate solution. The organic phase was isolated andconcentrated. The concentrate was flash chromatographed on silica gelwith 10-30% ethyl acetate/hexanes.

Example 50D tert-butyl2-(4-carboxy-3-fluorophenyl)pyrrolidine-1-carboxylate

A mixture of EXAMPLE 50C (5.5 g) and lithium hydroxide monohydrate (1.43g) in THF (50 mL) and water (50 mL) was titrated with methanol untiltransparent, stirred at ambient temperature for 2 hours, acidified to pH2 with 2M HCl, concentrated to about 40 mL and filtered.

Example 50E tert-butyl2-(4-(4-carbamoyl-1H-benzimidazol-2-yl)-3-fluorophenyl)pyrrolidine-1-carboxylate

To a solution of EXAMPLE 50D (1.48 g) in pyridine (5 mL) and DMF (5 mL)was added CDI (0.856 g). The solution was stirred at 45° C. for 2 hours,treated with 2,3-diaminobenzamide dihydrochloride (1.08 g), stirred atambient temperature for 18 hours and concentrated. The concentrate wasdissolved in acetic acid (30 mL), and this solution was heated at 80° C.for 3 hours and concentrated. The concentrate was dissolved in ethylacetate, washed with sodium bicarbonate solution and brine andconcentrated. The concentrate was flash chromatographed on silica gelwith 0-15% methanol in 2:1 ethyl acetate/hexane.

Example 50F2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 50E (1.5 g) in dichloromethane (50 mL) was treatedwith TFA (10 mL), stirred for 1 hour and concentrated. The concentratewas purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A:0.1% TFA in water; B: 0.1% TFA in CH₃CN, 0-100% gradient). ¹H NMR(CD₃OD) δ 2.21-2.36 (m, 3H), 2.54-2.63 (m, 1H), 3.47-3.59 (m, 2H), 4.76(dd, J=9.51, 7.06 Hz, 1H), 7.43 (t, J=7.83 Hz, 1H), 7.50-7.55 (m, 2H),7.84 (d, J=7.36 Hz, 1H), 7.98 (d, J=7.67 Hz, 1H), 8.42 (t, J=8.13 Hz,1H).

Example 50G2-(4-(1-ethylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

To a solution of EXAMPLE 50F (150 mg) in methanol (6 mL) was addedtriethylamine (125 mL) and 32 wt/v % acetaldehyde in water (210 mL). Thesolution was stirred for 1 hour, treated with sodium cyanoborohydride(95 mg), stirred for 3 hours at ambient temperature and at 50° C. for 18hours and concentrated. The concentrate was purified by HPLC (Zorbax,C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA inCH₃CN; 0-100% gradient). ¹H NMR (CD₃OD) δ 1.31-1.36 (m, 3H), 2.30-2.42(m, 2H), 2.61-2.70 (m, 1H), 3.17-3.29 (m, 2H), 3.34-3.41 (m, 1H),3.52-3.62 (m, 1H), 3.94-4.01 (m, 1H), 4.64-4.73 (m, 1H), 7.75 (t, J=7.98Hz, 1H), 7.87 (d, J=7.67 Hz, 1H), 7.93 (d, J=11.35 Hz, 1H), 8.07 (d,J=7.98 Hz, 1H), 8.13 (d, J=7.67 Hz, 1H), 8.28 (t, J=7.52 Hz, 1H).

Example 512-(2-fluoro-4-(1-isopropylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

To a solution of EXAMPLE 50F (80 mg) in methanol (3 mL) was addedtriethylamine (67 mL) and acetone (35 mL). This solution was stirred atambient temperature for 1 hour, treated with sodium cyanoborohydride (30mg), stirred at 50° C. for 18 hours and concentrated. The concentratewas purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A:0.1% TFA in water; B: 0.1% TFA in CH₃CN; 0-100% gradient). ¹H NMR(CD₃OD) δ 1.33 (d, J=6.71 Hz, 3H), 1.35 (d, J=6.71 Hz, 3H), 2.25-2.34(m, 3H), 2.58-2.64 (m, 1H), 3.47-3.61 (m, 2H), 3.67-3.74 (m, 1H),4.72-4.79 (m, 1H), 7.45 (t, J=7.78 Hz, 1H), 7.63 (d, J=8.24 Hz, 1H),7.66 (d, J=11.90 Hz, 1H), 7.86 (d, J=8.24 Hz, 1H), 8.00 (d, J=7.32 Hz,1H), 8.48 (t, J=7.78 Hz, 1H).

Example 522-(4-(1-Cyclobutylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 51 andsubstituting cyclobutanone for acetone. ¹H NMR (CD₃OD) δ 1.74-1.82 (m,3H), 1.93-1.99 (m, 1H), 2.25-2.40 (m, 6H), 2.59-2.65 (m, 1H), 3.76-3.82(m, 1H), 3.93-3.98 (m, 1H), 4.53-4.57 (m, 1H), 7.46 (t, J=7.78 Hz, 1H),7.62 (d, J=8.24 Hz, 1H), 7.65 (d, J=11.90 Hz, 1H), 7.86 (d, J=7.93 Hz,1H), 8.01 (d, J=7.63 Hz, 1H), 8.45 (t, J=7.93 Hz, 1H).

Example 532-(2-Fluoro-4-(1-propylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 51 andsubstituting propionaldehyde for acetone. ¹H NMR (CD₃OD) δ 0.94 (t,J=7.32 Hz, 3H), 1.61-1.69 (m, 1H), 1.71-1.81 (m, 1H), 2.29-2.37 (m, 3H),2.62 (m, 1H), 3.04-3.14 (m, 2H), 3.34-3.41 (m, 1H), 3.90-3.96 (m, 1H),4.53-4.60 (m, 1H), 7.45 (t, J=7.93 Hz, 1H), 7.61 (d, J=8.24 Hz, 1H),7.64 (d, J=11.90 Hz, 1H), 7.86 (d, J=7.63 Hz, 1H), 8.00 (d, J=7.63 Hz,1H), 8.46 (t, J=7.78 Hz, 1H).

Example 542-(4-(1-cyclopropylmethylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 51 andsubstituting cyclopropanecarboxaldehyde for acetone. ¹H NMR (CD₃OD) δ0.24-0.30 (m, 1H), 0.38-0.42 (m, 1H), 0.63-0.71 (m, 2H), 1.00-1.09 (m,1H), 2.30-2.38 (m, 3H), 2.62-2.67 (m, 1H), 3.01-3.09 (m, 2H), 3.42-3.48(m, 1H), 4.00-4.07 (m, 1H), 4.59 (t, J=8.39 Hz, 1H), 7.45 (t, J=7.93 Hz,1H), 7.60 (d, J=8.24 Hz, 1H), 7.62 (d, J=12.21 Hz, 1H), 7.86 (d, J=7.93Hz, 1H), 8.00 (d, J=7.63 Hz, 1H), 8.47 (t, J=7.78 Hz, 1H).

Example 556-fluoro-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamideExample 55A tert-butyl2-(4-(4-carbamoyl-6-fluoro-1H-benzimidazol-2-yl)-3-fluorophenyl)pyrrolidine-1-carboxylate

A solution of EXAMPLE 50D (700 mg) in dichloromethane (8 mL) was treatedwith oxalyl chloride (296 μL) and DMF (one drop), stirred for 1 hour andconcentrated. The concentrate was dissolved in dichloromethane (8 mL),and this solution was added to a solution of EXAMPLE 45D (382 mg) andtriethylamine (378 μL) in THF (8 mL). The mixture was stirred for 18hours and concentrated. The concentrate was dissolved in acetic acid (15mL), heated at 80° C. for 3 hours and concentrated. The concentrate waspartitioned between ethyl acetate and sodium bicarbonate solution theethyl acetate layer washed with sodium bicarbonate solution andconcentrated. The concentrate was flash chromatographed on silica gelwith 3:2 ethyl acetate/hexanes.

Example 55B6-fluoro-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 55A (360 mg) in dichloromethane (25 mL) andtrifluoroacetic acid (5 mL) was stirred for 1 hour and concentrated. Theconcentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobilephase A: 0.1% TFA in water; B: 0.1% TFA in CH₃CN; 0-100% gradient). ¹HNMR (CD₃OD) δ 2.20-2.37 (m, 3H), 2.56-2.62 (m, 1H), 3.47-3.57 (m, 2H),4.76 (dd, J=9.31, 7.17 Hz, 1H), 7.50-7.54 (m, 3H), 7.71 (dd, J=10.37,2.44 Hz, 1H), 8.43 (t, J=7.93 Hz, 1H).

Example 566-fluoro-2-(2-fluoro-4-(1-isopropylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 23 andsubstituting EXAMPLE 55 for EXAMPLE 18. ¹H NMR (CD₃OD) δ 1.36 (dd,J=6.41, 2.44 Hz, 6H), 2.25-2.35 (m, 3H), 2.57-2.65 (m, 1H), 3.45-3.59(m, 2H), 3.66-3.73 (m, 1H), 4.73-4.77 (m, 1H), 7.52 (dd, J=8.24, 2.44Hz, 1H), 7.60-7.66 (m, 2H), 7.71 (dd, J=10.53, 2.59 Hz, 1H), 8.47 (t,J=7.93 Hz, 1H).

Example 572-(4-(1-Ethylpyrrolidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 55 for EXAMPLE 50F. ¹H NMR (CD₃OD) δ 1.31 (t,J=7.21 Hz, 3H), 2.29-2.38 (m, 2H), 2.58-2.68 (m, 1H), 3.11-3.21 (m, 1H),3.26-3.40 (m, 2H), 3.51-3.78 (m, 1H), 3.88-3.95 (m, 1H), 4.53-4.59 (m,1H), 7.52 (dd, J=8.13, 2.61 Hz, 1H), 7.56-7.64 (m, 2H), 7.71 (dd,J=10.43, 2.45 Hz, 1H), 8.46 (t, J=7.82 Hz, 1H).

Example 586-Fluoro-2-(2-fluoro-4-(1-methylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting Example 55 for EXAMPLE 50F and formaldehyde foracetaldehyde. ¹H NMR (CD₃OD) δ 2.28-2.43 (m, 3H), 2.61-2.69 (m, 1H),2.88 (s, 3H), 3.32-3.40 (m, 1H), 3.88-3.96 (m, 1H), 4.48-4.54 (m, 1H),7.53 (dd, J=8.29, 2.45 Hz, 1H), 7.57-7.63 (m, 2H), 7.72 (dd, J=10.43,2.46 Hz, 1H), 8.47 (t, J=7.82 Hz, 1H).

Example 596-fluoro-2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamideExample 59A methyl 2-fluoro-4-pyridin-3-yl-benzoate

A mixture of EXAMPLE 50A (5 g), 3-pyridinylboronic acid (4 g) anddichlorobis(triphenylphosphine)-palladium (II) (1.1 g) in 7:3:2DME/water/ethanol (200 mL) and 2M aqueous Na₂CO₃ solution (1 mL) at 80°C. was stirred 18 hours, cooled and filtered. The filtrate waspartitioned between ethyl acetate and water, and the ethyl acetate layerwashed with water and concentrated. The concentrate was flashchromatographed on silica gel with 1:2 ethyl acetate/hexanes.

Example 59B benzyl3-(4-methoxycarbonyl-3-fluorophenyl)piperidine-1-carboxylate

Example 59A (4.5 g) was hydrogenated with catalytic 5% Pt/C under 60 psiof hydrogen as described for EXAMPLE 26. To a mixture of this productand potassium carbonate (4 g) in dioxane (50 mL) and water (30 mL) wasadded benzyl chlorofomate (2.8 mL). The mixture was stirred at ambienttemperature for 4 hours, treated with piperazine, stirred for 30 minutesand concentrated. The concentrate was partitioned between ethyl acetateand dilute hydrochloric acid and the ethyl acetate layer washed withwater and concentrated. The concentrate was flash chromatographed onsilica gel with 1:2 ethyl acetate/hexanes.

Example 59C benzyl 3-(4-carboxy-3-fluorophenyl)piperidine-1-carboxylate

This compound was prepared according to the procedure for EXAMPLE 50Dand substituting EXAMPLE 59B for EXAMPLE 50C.

Example 59D benzyl3-(4-(4-carbamoyl-6-fluoro-1H-benzimidazol-2-yl)-3-fluorophenyl)piperidine-1-carboxylate

A solution of EXAMPLE 59C (1.1 g) in dichloromethane (20 mL) was treatedwith oxalyl chloride (240 μL) and DMF (one drop), stirred for 1 hour andconcentrated. The concentrate was dissolved in dichloromethane (10 mL),and this solution was added into a solution of EXAMPLE 45D (450 mg) andtriethylamine (2 mL) in THF (10 mL), stirred at ambient temperature for18 hours and concentrated. The concentrate was dissolved in acetic acid(15 mL), heated at 80° C. for 3 hours, cooled and concentrated. Theconcentrate was partitioned between ethyl acetate and sodium bicarbonatesolution, and the ethyl acetate layer washed with sodium bicarbonatesolution and concentrated. The concentrate was flash chromatographed onsilica gel with ethyl acetate.

Example 59E6-fluoro-2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 59D (150 mg) in TFA (10 mL) at 40° C. was stirredfor 2.5 days and concentrated. The concentrate was purified by HPLC(Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in water; B:0.1% TFA in CH₃CN; 0-100% gradient). ¹H NMR (CD₃OD) δ 1.83-1.96 (m, 2H),2.07-2.15 (m, 2H), 3.02-3.21 (m, 3H), 3.44-3.54 (m, 2H), 7.32 (dd,J=4.14, 1.69 Hz, 1H), 7.35 (s, 1H), 7.50 (dd, J=8.29, 2.45 Hz, 1H), 7.69(dd, J=10.43, 2.45 Hz, 1H), 8.30 (t, J=7.98 Hz, 1H).

Example 606-chloro-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamideExample 60A methyl 2-fluoro-4-pyridin-2-yl-benzoate

To a suspension of EXAMPLE 50A (5 g), Pd₂(dba)₃ (1.5 g) andtri-2-furylphosphine (1.5 g) in DMF (100 mL) was added2-trimethylstannyl pyridine (9.5 g) and triethylamine (2 mL). Thereaction mixture was stirred at 80° C. for 18 hours, cooled andpartitioned between ethyl acetate and brine. The ethyl acetate layer wasseparated and concentrated, and the concentrate flash chromatographed onsilica gel with 1:2 ethyl acetate/hexanes.

Example 60B benzyl 2-(4-carboxy-3-fluorophenyl)piperidine-1-carboxylate

This compound was prepared according to the procedure for EXAMPLE 59Cand substituting EXAMPLE 60A for EXAMPLE 59A.

Example 60C6-chloro-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 59 andsubstituting EXAMPLE 60B for EXAMPLE 59C and EXAMPLE 44B for EXAMPLE45D. ¹H NMR (CD₃OD) δ 1.77-1.88 (m, 2H), 1.95-2.12 (m, 3H), 2.15-2.22(m, 1H), 3.19-3.28 (m, 1H), 3.51-3.58 (m, 1H), 4.39 (dd, J=12.27, 2.76Hz, 1H), 7.51 (d, J=10.13 Hz, 2H), 7.78 (d, J=1.84 Hz, 1H), 7.91 (d,J=2.15 Hz, 1H), 8.44 (t, J=7.82 Hz, 1H).

Example 616-fluoro-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 60 andsubstituting EXAMPLE 45D for EXAMPLE 44B. ¹H NMR (CD₃OD) δ 1.78-1.89 (m,2H), 1.98-2.09 (m, 3H), 2.15-2.21 (m, 1H), 3.21-3.26 (m, 1H), 3.54 (d,J=12.51 Hz, 1H), 4.39 (dd, J=12.21, 2.44 Hz, 1H), 7.49-7.53 (m, 3H),7.70 (dd, J=10.37, 2.44 Hz, 1H), 8.43 (t, J=7.78 Hz, 1H).

Example 626-fluoro-2-(2-fluoro-4-(1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 59 for EXAMPLE 50F and formaldehyde foracetaldehyde ¹H NMR (CD₃OD) δ 1.77-1.83 (m, 1H), 1.92-2.02 (m, 1H),2.09-2.18 (m, 2H), 2.95 (s, 3H), 3.02-3.10 (m, 1H), 3.16-3.21 (m, 2H),3.61 (d, J=12.21 Hz, 1H), 3.65 (d, J=7.93 Hz, 1H), 7.33 (d, J=4.58 Hz,1H), 7.34 (s, 1H), 7.50 (dd, J=8.24, 2.44 Hz, 1H), 7.69 (dd, J=10.37,2.44 Hz, 1H), 8.29 (t, J=7.93 Hz, 1H).

Example 632-(4-(1-ethylpiperidin-2-yl)-3-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 59 for EXAMPLE 50F. ¹H NMR (CD₃OD) δ 1.40 (t,J=7.32 Hz, 3H), 1.80-1.88 (m, 1H), 1.91-2.02 (m, 1H), 2.08-2.20 (m, 2H),2.97-3.04 (m, 1H), 3.12-3.21 (m, 1H), 3.26 (q, J=7.32 Hz, 2H), 3.63-3.71(m, 2H), 7.32-7.37 (m, 2H), 7.50 (dd, J=8.24, 2.44 Hz, 1H), 7.69 (dd,J=10.37, 2.44 Hz, 1H), 8.29 (t, J=7.93 Hz, 1H).

Example 646-fluoro-2-(2-fluoro-4-(1-isopropyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 59 for EXAMPLE 50F and acetone for acetaldehyde. ¹HNMR (CD₃OD) δ 1.42 (dd, J=6.56, 3.51 Hz, 6H), 1.79-1.90 (m, 1H),1.94-2.05 (m, 1H), 2.11 (d, J=13.73 Hz, 1H), 2.18 (d, J=14.65 Hz, 1H),3.08-3.15 (m, 1H), 3.19-3.26 (m, 2H), 3.51-3.63 (m, 3H), 7.35 (s, 1H),7.37 (d, J=7.02 Hz, 1H), 7.49 (dd, J=8.24, 2.44 Hz, 1H), 7.68 (dd,J=10.68, 2.44 Hz, 1H), 8.28 (t, J=8.09 Hz, 1H).

Example 652-(4-(1-cyclobutylpiperidin-3-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 59 for EXAMPLE 50F and cyclobutanone foracetaldehyde. ¹H NMR (CD₃OD) δ 1.76-1.97 (m, 4H), 2.14 (t, J=15.71 Hz,2H), 2.25-2.43 (m, 4H), 2.79-2.87 (m, 1H), 2.99 (t, J=12.36 Hz, 1H),3.10-3.18 (m, 1H), 3.57 (d, J=11.90 Hz, 2H), 3.66-3.75 (m, 1H), 7.35 (d,J=10.07 Hz, 2H), 7.50 (dd, J=8.24, 2.44 Hz, 1H), 7.70 (dd, J=10.37, 2.44Hz, 1H), 8.31 (t, J=7.93 Hz, 1H).

Example 676-chloro-2-(2-fluoro-4-(1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 60 for EXAMPLE 50F and formaldehyde foracetaldehyde. ¹H NMR (CD₃OD) δ 1.73-1.82 (m, 1H), 1.94-2.22 (m, 5H),2.68 (s, 3H), 3.21-3.28 (m, 1H), 3.69-3.77 (m, 1H), 4.29 (dd, J=11.44,3.81 Hz, 1H), 7.52-7.57 (m, 2H), 7.76 (d, J=2.14 Hz, 1H), 7.87 (d,J=1.83 Hz, 1H), 8.45 (t, J=7.93 Hz, 1H).

Example 686-chloro-2-(4-(1-ethylpiperidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 60 for EXAMPLE 50F. ¹H NMR (CD₃OD) δ 1.26 (t,J=7.32 Hz, 3H), 1.75-1.82 (m, 1H), 1.94-2.07 (m, 2H), 2.08-2.21 (m, 3H),2.92-3.02 (m, 1H), 3.06-3.14 (m, 1H), 3.14-3.22 (m, 1H), 3.80 (d,J=12.82 Hz, 1H), 4.40 (dd, J=11.44, 3.51 Hz, 1H), 7.53-7.58 (m, 2H),7.77 (d, J=2.14 Hz, 1H), 7.88 (d, J=2.14 Hz, 1H), 8.46 (t, J=7.78 Hz,1H).

Example 696-chloro-2-(4-(1-cyclopropylmethyl-piperidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 60 for EXAMPLE 50F and cyclopropylaldehyde foracetaldehyde. ¹H NMR (CD₃OD) δ 0.21-0.27 (m, 1H), 0.27-0.35 (m, 1H),0.66-0.79 (m, 2H), 1.00-1.10 (m, 1H), 1.74-1.84 (m, 1H), 1.99-2.09 (m,2H), 2.09-2.21 (m, 3H), 2.79 (dd, J=13.58, 7.48 Hz, 1H), 2.93 (dd,J=13.58, 6.87 Hz, 1H), 3.23-3.32 (m, 1H), 4.05 (d, J=11.90 Hz, 1H), 4.40(dd, J=11.14, 3.81 Hz, 1H), 7.51-7.57 (m, 2H), 7.77 (d, J=1.83 Hz, 1H),7.88 (d, J=1.83 Hz, 1H), 8.47 (t, J=7.93 Hz, 1H).

Example 702-(4-(1-ethylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 61 for EXAMPLE 50F. ¹H NMR (CD₃OD) δ 1.26 (t,J=7.36 Hz, 3H), 1.74-1.84 (m, 1H), 1.92-2.20 (m, 5H), 2.96 (dd, J=13.35,7.21 Hz, 1H), 3.06-3.14 (m, 1H), 3.14-3.23 (m, 1H), 3.79 (d, J=12.58 Hz,1H), 4.39 (dd, J=11.20, 3.84 Hz, 1H), 7.50-7.58 (m, 3H), 7.71 (dd,J=10.59, 2.61 Hz, 1H), 8.48 (t, J=7.93 Hz, 1H).

Example 712-(4-(1-cyclopropylmethylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 61 for EXAMPLE 50F and cyclopropylaldehyde foracetaldehyde. ¹H NMR (CD₃OD) δ 0.21-0.27 (m, 1H), 0.28-0.35 (m, 1H),0.66-0.78 (m, 2H), 1.01-1.13 (m, 1H), 1.75-1.86 (m, 1H), 1.97-2.20 (m,5H), 2.76-2.83 (m, 1H), 2.91-2.96 (m, 1H), 3.23-3.31 (m, 1H), 4.04 (d,J=12.58 Hz, 1H), 4.40 (dd, J=10.13, 4.91 Hz, 1H), 7.50-7.58 (m, 3H),7.70 (dd, J=10.59, 2.61 Hz, 1H), 8.45 (t, J=8.13 Hz, 1H).

Example 726-fluoro-2-(2-fluoro-4-(1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 50 andsubstituting EXAMPLE 61 for EXAMPLE 50F and formaldehyde foracetaldehyde. ¹H NMR (CD₃OD) δ 1.73-1.82 (m, 1H), 1.93-2.20 (m, 5H),2.68 (s, 3H), 3.21-3.29 (m, 1H), 3.72 (d, J=13.43 Hz, 1H), 4.29 (dd,J=11.75, 3.51 Hz, 1H), 7.52-7.57 (m, 3H), 7.72 (dd, J=10.53, 2.59 Hz,1H), 8.48 (t, J=7.93 Hz, 1H).

Example 736-chloro-2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to the procedure for EXAMPLE 59 andsubstituting EXAMPLE 44B for EXAMPLE 45D. ¹H NMR (CD₃OD) δ 1.86-2.01 (m,2H), 2.08-2.16 (m, 2H), 3.05-3.13 (m, 1H), 3.20-3.28 (m, 2H), 3.48 (d,J=12.51 Hz, 1H), 3.53 (d, J=7.93 Hz, 1H), 7.50-7.55 (m, 2H), 8.01 (d,J=1.83 Hz, 1H), 8.11 (d, J=1.83 Hz, 1H), 8.18 (t, J=7.93 Hz, 1H).

Example 746-chloro-2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamideExample 74A tert-butyl4-(4-(2-amino-3-carbamoyl-5-chlorophenylcarbamoyl)phenyl)piperidine-1-carboxylate

A solution of 2,3-diamino-5-chlorobenzamide (0.75 g), tert-butyl4-(4-carboxyphenyl)-piperidine-1-carboxylate (0.17 g),1-hydroxybenzotriazole (HOBT, 0.22 g),benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP, 0.85 g) and diisopropylethylamine (DIPEA, 0.85 mL) in DMF (5 mL)was stirred for 18 hours and concentrated. The concentrate was flashchromatographed on silica gel with 10% methanol/dichloromethane.

Example 74B6-chloro-2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 74A (60 mg) in acetic acid (5 mL) at reflux wasstirred for 60 minutes and concentrated. The concentrate was purified bychromatography on silica gel with 10% methanol/dichloromethane. ¹H NMR(DMSO-d₆) δ 9.24 (s, 1H), 8.22 (d, J=7.98 Hz, 2H), 7.96 (s, 1H),7.75-7.84 (m, 2H), 7.46 (d, J=8.29 Hz, 2H), 3.41 (d, J=12.27 Hz, 2H),2.99-3.08 (m, 2H), 2.96 (t, J=3.53 Hz, 1H), 2.01 (d, J=12.27 Hz, 2H),1.79-1.90 (m, 2H).

Example 752-(2-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide

A solution of EXAMPLE 26 (40 mg) and 37 wt % formaldehyde in water (45mL) in methanol (3 mL) at ambient temperature was stirred for 1 hour,treated with sodium cyanoborohydride (38 mg), stirred at 50° C. for 18hours, cooled and concentrated. The concentrate purified by HPLC (ZorbaxC-8, 0.1% TFA/CH₃CN/water). The TFA salt was converted to the HCl saltby dissolving in methanol and treating with HCl in diethyl ether. ¹H NMR(CD₃OD) δ 2.01-2.15 (m, 2H), 2.17-2.27 (m, 2H), 2.95 (s, 3H), 3.08-3.16(m, 1H), 3.17-3.26 (m, 2H), 3.67 (d, J=12.58 Hz, 2H), 7.43-7.51 (m, 2H),7.64 (t, J=7.98 Hz, 1H), 7.98 (d, J=7.98 Hz, 1H), 8.07 (dd, J=7.52, 0.77Hz, 1H), 8.19 (t, J=7.98 Hz, 1H).

Example 766-chloro-2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting tert-butyl3-(4-carboxyphenyl)piperidine-1-carboxylate for tert-butyl4-(4-carboxyphenyl)piperidine-1-carboxylate in EXAMPLE 74. ¹H NMR(DMSO-D6) δ 9.22 (s, 1H), 8.23 (d, J=8.29 Hz, 2H), 7.95 (s, 1H),7.76-7.80 (m, 2H), 7.53 (d, J=7.98 Hz, 2H), 3.36-3.41 (m, 1H), 2.99-3.10(m, 3H), 2.92 (s, 1H), 1.91-1.97 (m, 2H), 1.75-1.85 (m, 3H).

Example 776-fluoro-2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting 2,3-diamino-5-fluorobenzamidefor 2,3-diamino-5-chlorobenzamide in EXAMPLE 76. ¹H NMR (DMSO-D6) δ 9.22(s, 1H), 8.22 (d, J=8.29 Hz, 2H), 7.94 (s, 1H), 7.55-7.62 (m, 2H), 7.51(d, J=8.29 Hz, 2H), 3.02-3.12 (m, 3H), 2.90 (s, 1H), 1.91-1.97 (m, 2H),1.75-1.86 (m, 3H).

Example 782-(4-(1-ethylpiperidin-4-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to procedure for EXAMPLE 75 andsubstituting acetaldehyde for formaldehyde. ¹H NMR (CD₃OD) δ 1.44 (t,J=7.52 Hz, 3H), 1.74-1.87 (m, 1H), 2.05-2.20 (m, 2H), 2.20-2.32 (m, 2H),3.11-3.21 (m, 1H), 3.56-3.67 (m, 3H), 3.69-3.78 (m, 1H), 3.79-3.88 (m,1H), 7.46-7.54 (m, 2H), 7.68 (t, J=7.98 Hz, 1H), 8.01 (d, J=7.98 Hz,1H), 8.09 (dd, J=7.52, 0.77 Hz, 1H), 8.17 (t, J=7.82 Hz, 1H).

Example 792-(2-fluoro-4-(1-isopropylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to procedure for EXAMPLE 75 andsubstituting acetone for formaldehyde ¹H NMR (CD₃OD) δ 1.44 (d, J=6.75Hz, 6H), 2.13-2.29 (m, 4H), 3.10-3.20 (m, 1H), 3.21-3.29 (m, 2H),3.54-3.68 (m, 3H), 7.49-7.56 (m, 2H), 7.69-7.76 (m, 1H), 8.04 (dd,J=8.29, 0.61 Hz, 1H), 8.11 (dd, J=7.67, 0.61 Hz, 1H), 8.12-8.17 (m, 1H).

Example 806-chloro-2-(4-(1-cyclopropylmethylpiperidin-3-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to procedure for EXAMPLE 75 andsubstituting Example 73 for EXAMPLE 26 and cyclopropylaldehyde forformaldehyde. ¹H NMR (CD₃OD) δ 0.43-0.50 (m, 2H), 0.75-0.84 (m, 2H),1.14-1.24 (m, 1H), 1.80-1.88 (m, 1H), 1.95-2.06 (m, 1H), 2.15 (t,J=16.78 Hz, 2H), 3.00-3.12 (m, 3H), 3.15-3.26 (m, 2H), 3.76 (d, J=7.63Hz, 2H), 7.33 (d, J=9.76 Hz, 2H), 7.75 (d, J=1.83 Hz, 1H), 7.87 (d,J=1.83 Hz, 1H), 8.29 (t, J=7.93 Hz, 1H).

Example 816-Fluoro-2-(2-fluoro-4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared according to procedure for EXAMPLE 60 andsubstituting Example 45D for EXAMPLE 44B and 4-tributylstannylpyridinefor 2-trimethylstannylpyridine. ¹H NMR (CD₃OD) δ 1.90-2.00 (m, 2H), 2.15(d, J=14.04 Hz, 2H), 3.00-3.07 (m, 1H), 3.14-3.21 (m, 2H), 3.55 (d,J=12.82 Hz, 2H), 7.25 (d, J=12.82 Hz, 1H), 7.29 (d, J=7.93 Hz, 1H), 7.48(dd, J=8.24, 2.44 Hz, 1H), 7.67 (dd, J=10.68, 2.44 Hz, 1H), 8.23 (t,J=7.93 Hz, 1H).

Example 826-Chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamideExample 82A 4-(1-methylpiperidin-4-yl)benzoic acid

A solution of 4-piperidin-4-ylbenzoic acid (0.5 g) and 36% formaldehydein water (0.175 mL) in methanol (5 mL) was treated with sodiumcyanoborohydride (0.13 g) and acetic acid (0.5 mL), stirred for 18 hoursand concentrated. The concentrate was flash chromatographed on silicagel with 10% methanol/dichloromethane.

Example 82B6-chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide

A mixture of EXAMPLE 82A (0.089 g) and thionyl chloride (1 mL) wasstirred for 18 hours at ambient temperature and concentrated. Theconcentrate was substituted for tert-butyl4-(4-carboxyphenyl)piperidine-1-carboxylate in EXAMPLE 74. ¹H NMR(DMSO-d₆) δ 9.14 (s, 1H), 8.24 (d, J=8.29 Hz, 2H), 7.93 (s, 1H),7.76-7.80 (m, 2H), 7.47 (d, J=8.29 Hz, 2H), 3.51 (d, J=11.97 Hz, 2H),3.02-3.08 (m, 2H), 2.86-2.95 (m, 1H), 2.79 (d, J=4.91 Hz, 3H), 1.99-2.07(m, 3H).

Example 836-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting 2,3-diamino-5-fluorobenzamidefor 2,3-diamino-5-chlorobenzamide in EXAMPLE 82. ¹H NMR (DMSO-D6) δ 9.64(d, J=8.40 Hz, 2H), 9.10 (dd, J=10.72, 2.61 Hz, 1H), 9.02 (dd, J=8.26,2.46 Hz, 1H), 8.97 (d, J=8.11 Hz, 2H), 4.94-4.98 (m, 2H), 4.56-4.60 (m,2H), 4.41-4.47 (m, 1H), 4.28 (s, 3H) 3.54-3.58 (m, 2H) 3.45-3.51 (m,2H).

Example 846-fluoro-2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared by substituting tert-butyl2-(4-carboxyphenyl)piperidine-1-carboxylate for tert-butyl4-(4-carboxyphenyl)piperidine-1-carboxylate in EXAMPLE 77. ¹H NMR(DMSO-D6) δ 9.21 (s, 1H), 8.32 (d, J=8.59 Hz, 2H), 7.94 (s, 1H), 7.76(d, J=8.29 Hz, 2H), 7.58-7.64 (m, 2H), 4.33 (s, 1H), 3.38 (s, 2H), 3.07(s, 1H), 1.98 (s, 1H), 1.88-1.95 (m, 2H), 1.83 (d, J=2.45 Hz, 2H), 1.68(s, 1H).

Example 856-fluoro-4-(1-methylpiperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

This compound was prepared from EXAMPLE 84 using the conditionsdescribed in EXAMPLE 82A. ¹H NMR (DMSO-D6) δ 9.31 (d, J=2.44 Hz, 1H),8.17 (d, J=7.93 Hz, 2H), 7.96 (d, J=2.75 Hz, 1H), 7.51-7.60 (m, 4H),2.97 (s, 1H), 2.86 (s, 1H), 2.07 (s, 1H), 1.89-1.98 (m, 4H), 1.76 (s,1H), 1.65 (s, 3H), 1.46 (s, 1H), 1.35 (s, 1H).

Example 86(+)-(R)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamideExample 86A benzyl(R)-3-(4-methoxycarbonyl-3-fluorophenyl)piperidine-1-carboxylate

1 g of racemic EXAMPLE 60A was resolved on HPLC (Chiralcel OJ,85:7.5:7.5 hexane/EtOH/MeOH) to afford 448 mg of the title compound asthe faster-eluting R-enantiomer (100% e.e.) and 460 mg of theS-enantiomer (98% e.e.) as the slower-eluting fraction. MS (DCI): m/z372 (M+H)⁺.

Example 86B benzyl(R)-2-(4-carboxy-3-fluorophenyl)piperidine-1-carboxylate

This compound was prepared according to the procedure for EXAMPLE 60B,substituting EXAMPLE 86A for EXAMPLE 60A. MS (DCI): m/z 358 (M+H)⁺.

Example 86C benzyl(R)-2-[4-(2-amino-3-carbamoylphenylcarbamoyl)-3-fluorophenyl]piperidine-1-carboxylate

A solution of EXAMPLE 86B (440 mg, 1.23 mmol) in a mixture of pyridine(5 mL) and DMF (5 mL) was treated with CDI (240 mg, 1.48 mmol) at 40° C.for 30 minutes. 2,3-Diamino-benzamide dihydrochloride (275 mg, 1.23mmol) was added and the mixture was stirred at ambient temperatureovernight. After concentration, the residue was partitioned betweenethyl acetate and dilute aqueous sodium bicarbonate solution. The lightyellow solid was collected by filtration, washed with water and ethylacetate, and dried to give the title compound, which was used withoutfurther purification. MS (DCI/NH₃) m/z 491 (M+H)⁺.

Example 86Dbenzyl-(R)-2-[4-carbamoyl-1H-benzimidazol-2-yl)-3-fluorophenyl]piperidine-1-carboxylate

A suspension of EXAMPLE 86C in acetic acid (15 mL) was heated underreflux for 2 hours. After cooling, the solution was concentrated and theresidue partitioned between ethyl acetate and aqueous sodium bicarbonatesolution. The organic phase was washed with water, concentrated andpurified by flash column chromatography (EtOAc) to provide 300 mg oftitle compound. MS (DCI/NH₃) m/z 473 (M+H)⁺.

Example 86E(+)-(R)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE26, substituting EXAMPLE 86D for EXAMPLE 26B. [α]⁵⁸⁹=+3.0. ¹H NMR(CD₃OD) δ 1.77-1.97 (m, 2H); 1.97-2.13 (m, 3H); 2.16-2.24 (m, 1H);3.20-3.30 (m, 1H); 3.56 (d, J=12.89 Hz, 1H); 4.49 (d, J=11.66 Hz, 1H);7.66-7.73 (m, 3H); 8.02 (d, J=8.29 Hz, 1H); 8.11 (d, J=7.67 Hz, 1H);8.30 (t, J=7.82 Hz, 1H).

Example 87(−)-(S)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE86, using the slower-eluting S-enantiomer of EXAMPLE 86A in place of thefaster-eluting R-enantiomer. [α]⁵⁸⁹=−3.03. ¹H NMR (CD₃OD); δ 1.78-1.88(m, 1H); 1.90-2.13 (m, 3H); 2.19 (d, J=11.29 Hz, 1H); 3.22-3.33 (m, 2H);3.57 (d, J=12.82 Hz, 1H); 4.48-4.56 (m, 1H); 7.72-7.82 (m, 3H); 8.07 (d,J=8.24 Hz, 1H); 8.13 (d, J=7.63 Hz, 1H); 8.25 (t, J=7.63 Hz, 1H).EXAMPLE 87 was synthesized as described below: EXAMPLE 87

Example 87A tert-butyl 5-(4-bromo-3-fluorophenyl)-5-oxopentylcarbamate

To a solution of 1-bromo-2-fluoro-4-iodobenzene (44.22 g, 0.147 mol) intetrahydrofuran (160 mL) was added isopropylmagnesium chloride (2.0 Msolution in tetrahydrofuran, 73.5 mL) at 0° C. and the mixture stirredat 0° C. for 3 hours. This solution was cannulated into a solution of1-BOC-2-piperidone (24.4 g, 0.122 mol) in tetrahydrofuran (240 mL) at−78° C. and the mixture stirred at −78° C. for 1 hour. The solution waswarmed to ambient temperature and stirred for one hour before quenchingwith water. Hydrochloric acid (2N, 120 mL) was added and the mixturestirred at ambient temperature for 10 minutes. The mixture wasconcentrated and the residue partitioned between ethyl acetate andbrine. The organic layer was washed with brine, dried over magnesiumsulfate and filtered. Concentration afforded the crude product which wasrecrystallized from hexane and dichloromethane to give 33.95 g of thetitle compound as a white solid. ¹HNMR (CDCl₃) δ 1.44 (s, 9H), 1.52-1.63(m, 2H), 1.70-1.83 (m, 2H), 2.96 (t, J=7.1 Hz, 2H), 3.16 (q, J=6.4 Hz,2H), 4.58 (s, 1H), 7.59-7.71 (m, 3H).

Example 87B 6-(4-bromo-3-fluorophenyl)-2,3,4,5-tetrahydropyridine

A solution of EXAMPLE 87A (15.97 g, 42.67 mmol) in formic acid (200 mL)was heated at 40° C. for 5 hours. The reaction mixture was cooled,concentrated and the residue partitioned between ethyl acetate anddilute aqueous sodium hydroxide. The organic phase was washed withwater, dried over magnesium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel, using agradient of 20-60% ethyl acetate in hexane to give the title compound(9.5 g): MS (DCI): m/z 256, 258) (M+H)⁺.

Example 87C (S)-benzyl2-(4-bromo-3-fluorophenyl)piperidine-1-carboxylate

Example 87B (1.128 g, 4.4 mmol), bis(1,5-cyclooctadiene)diiridiumdichloride (28.9 mg, 0.043 mmol),(R)(+)-2,2-bis(di-p-tolylphosphino)-1,1-binaphthyl (60 mg, 0.0884 mmol),methanol (5 mL) and benzylamine (47.1 μL, 0.431 mmol) were combined in ascintillation vial in a dry, inverted stirred reactor. This reactor wasstirred magnetically for 45 minutes at ambient temperature under argonand was then pressurized with hydrogen. The mixture was stirred underhydrogen (900 psi) at ambient temperature for 3 days. Insoluble materialwas filtered off and filtrate concentrated. The residual oil wasdissolved in a mixture of dioxane and water and treated with potassiumcarbonate (1.21 g) and benzyl chloroformate (743 μL) at ambienttemperature overnight. The mixture was partitioned between ethyl acetateand brine. The organic phase was concentrated and the residue waspurified by flash chromatography on silica gel using a gradient of 5-20%ethyl acetate in hexane to give the title compound (1.47 g).

Example 87D (S)-benzyl2-(3-fluoro-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

A mixture of EXAMPLE 87C (1.46 g, 3.7 mmol),1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride (145 mg)and triethylamine (0.52 mL, 3.7 mmol) in methanol (16 mL) was stirredunder 60 psi of carbon monoxide at 100° C. for 1 hour. After cooling toambient temperature, the mixture was concentrated and the residuepurified by flash chromatography on silica gel using a gradient of10-40% ethyl acetate in hexane to give the title compound as a colorlessoil (1.215 g). [α]⁵⁸⁹=−102.2 (c=0.95 in methanol).

Example 87E(−)-(S)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE86, using EXAMPLE 87D in place of EXAMPLE 86A.

Example 886-fluoro-2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamideExample 88A tert butyl4-(4-(methoxy(methyl)carbamoyl)phenyl)piperidine-1-carboxylate

A mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (0.7g, 2.3 mmol), N,O-dimethylhydroxylamine (0.27 g, 2.8 mmol),1-hydroxybenzotriazole (0.37 g, 2.7 mmol) and1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (1.1 g, 5.8mmol) in tetrahydrofuran (15 mL) was stirred at ambient temperature for48 hours. Additional N,O-dimethylhydroxylamine (0.14 g, 1 mmol) wasadded and the mixture stirred an additional 4 hours and concentrated.The residue was dissolved in ethyl acetate, washed with water andfiltered through silica gel. The solution was concentrated and usedwithout further purification.

Example 88B tert butyl 4-(4-formylphenyl)piperidine-1-carboxylate

A solution of EXAMPLE 88A (0.8 g, 2.3 mmol) in tetrahydrofuran (5 mL)was cooled to −78° C. and treated with lithium aluminum hydride (0.25 g,6.6 mmol). The mixture was stirred for 30 minutes and treated with water(1 mL) and 15% sodium hydroxide (0.25 mL). Dichloromethane was added andthe mixture dried over magnesium sulfate and filtered through silicagel. The solution was concentrated and purified by flash chromatographyon silica gel using 1:1 hexane/ethyl acetate to provide the titlecompound (0.18 g).

Example 88C tert butyl4-(4-(4-carbamoyl-6-fluoro-1H-benzimidazol-2-yl)phenyl)piperidine-1-carboxylate

To a solution of EXAMPLE 45D (0.1 g, 0.6 mmol) and EXAMPLE 88B (0.18 g,0.6 mmol) in methanol (10 mL) was added 10% palladium on carbon (0.06 g)and the mixture refluxed overnight. The mixture was cooled, filteredthrough a pad of celite, concentrated and used without furtherpurification.

Example 88D6-fluoro-2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide

A mixture of EXAMPLE 88C (0.26 g, 0.6 mmol) in dichloromethane (5 mL)was treated with trifluoroacetic acid (5 mL) and the mixture stirred atambient temperature for 4 hours. The mixture was concentrated andpurified by flash chromatography on silica gel using 0-10%methanol/dichloromethane/0.1% ammonium hydroxide, followed by HPLC on aC18 column using 0-100% acetonitrile/water/0.1% trifluoroacetic acid, toprovide the title compound (0.131 g) as the trifluoroacetate salt. ¹HNMR(DMSO-D6) δ 9.22 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=8.3 Hz,2H), 7.94 (s, 1H), 7.55-7.62 (m, 2H), 7.45 (t, J=7.7 Hz, 2H), 3.40 (s,2H), 2.99-3.07 (m, 2H), 1.99 (s, 2H), 1.78-1.90 (m, 2H).

Example 89 (S)-2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

The title compound was isolated as a side product in the synthesis ofEXAMPLE 87. ¹HNMR (CD₃OD) δ 1.77-1.88 (m, 2H), 1.94-2.19 (m, 4H),3.21-3.27 (m, 1H), 3.53 (br d, J=12.8 Hz, 1H), 4.37 (dd, J=11.9, 2.7 Hz,1H), 7.46 (t, J=7.9 Hz, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.82 (d, J=7.3 Hz,1H), 7.98 (d, J=6.7 Hz, 1H), 8.28 (d, J=8.2 Hz, 2H).

Example 90 (R)-2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

The title compound was isolated as a side product in the synthesis ofEXAMPLE 86. ¹HNMR (CD₃OD) δ 1.75-1.87 (m, 2H), 1.95-2.19 (m, 4H),3.20-3.26 (m, 1H), 3.50-3.54 (m, 1H), 4.35-4.39 (m, 1H), 7.47 (t, J=7.9Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.81 (d, J=7.1 Hz, 1H), 7.98 (d, J=7.7Hz, 1H), 8.28 (d, J=8.2, 2H).

Example 916-fluoro-2-(4-(1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamideExample 91A 4-(1-(methylpiperidin-3-yl)benzoic acid

A mixture of 4-piperidin-3-ylbenzoic acid trifluoroacetate (0.32 g, 1.1mmol), sodium cyanoborohydride (0.066 g, 1.1 mmol), 36% aqueousformaldehyde (0.15 mL, 1.8 mmol) and acetic acid (0.5 mL) in methanol (4mL) was stirred overnight at ambient temperature. The mixture wasfiltered through silica gel, concentrated and used without furtherpurification.

Example 91B N-methoxy-N-methyl-4-(1-methylpiperidin-3-yl)benzamide

The title compound was prepared as described in EXAMPLE 88A bysubstituting Example 91A for4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid.

Example 91C 4-(1-methylpiperidin-3-yl)benzaldehyde

The title compound was prepared as described in EXAMPLE 88B bysubstituting EXAMPLE 91B for EXAMPLE 88A.

Example 91D6-fluoro-2-(4-(1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide

The title compound was prepared as described in Example 88C bysubstituting EXAMPLE 91C for EXAMPLE 88B. The crude product was purifiedby flash chromatography on silica gel with 0-10%methanol/dichloromethane/0.1% ammonium hydroxide to provide the titlecompound. ¹HNMR (DMSO-D6) δ 9.31 (s, 1H), 8.16 (d, J=8.2 Hz, 2H), 7.95(s, 1H), 7.59 (dd, J=10.7, 2.4 Hz, 1H), 7.56 (dd, J=8.4, 2.3 Hz, 1H),7.48 (d, J=8.2 Hz, 2H), 2.82-2.91 (m, 2H), 2.24 (s, 3H), 2.05 (t, J=10.1Hz, 1H), 1.98 (t, J=10.7 Hz, 1H), 1.80-1.88 (m, 1H), 1.73 (td, J=6.4,3.0 Hz, 1H), 1.64 (qt, J=12.5, 3.7 Hz, 1H) 1.45 (qd, J=12.2, 4.0 Hz,1H).

Example 92(+)(R)-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

Example 92A

(R)-tert-butyl2-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

To a solution of N—BOC-pyrrolidine (3.0 mL, 17.1 mmol) and (−)-sparteine(3.9 mL, 17.1 mmol) in tert-butyl methyl ether (36 mL) at −78° C. wasadded sec-butyl lithium (1.4 M solution in cyclohexane, 12.21 mL, 17.1mmol) and the mixture stirred at <−70° C. for 3 hours. A solution ofzinc (II) chloride (1M solution in diethyl ether, 10.2 mL, 10.2 mmol)was added, the mixture stirred at −78° C. for 30 minutes and then warmedto ambient temperature. The mixture was stirred for 30 minutes andEXAMPLE 50A (3.32 g, 14.25 mmol), t-butylphosphine-tetrafluoroboric acid(249 mg, 0.855 mmol) and palladium (II) acetate (153 mg, 0.69 mmol) wereadded and the mixture stirred at ambient temperature overnight.Concentrated ammonium hydroxide (1 mL) was added and the mixture stirredat ambient temperature for 30 minutes. Insoluble material was filteredthrough Celite and washed with ethyl acetate. The filtrate was washedwith 0.5 M hydrochloric acid and water and concentrated. The residue waspurified by flash chromatography on silica gel, using a gradient of10-30% ethyl acetate in hexane to give the title compound (2.66 g).

Example 92B(R)-4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-fluorobenzoic acid

To a solution of EXAMPLE 92A (2.65 g, 8.2 mmol) in tetrahydrofuran (20mL) was added lithium hydroxide monohydrate (688 mg, 16.4 mmol) in 20 mLof water and methanol added until a transparent solution formed. Thismixture was stirred at ambient temperature for 2 hours and acidifiedwith 2N hydrochloric acid to pH 2. The mixture was concentrated to about10 mL, diluted with water and let stand at ambient temperatureovernight. The white solid was collected by filtration, washed withwater and dried to give the title compound (2.21 g). Recrystallizationfrom methanol and water gave 1.61 g of title compound.

Example 92C(R)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLES50E and 50F, substituting EXAMPLE 92B for EXAMPLE 50D. Thetrifluoroacetate salt was dissolved in methanol and dichloromethane and1M hydrochloric acid in diethyl ether added. Concentration afforded thetitle compound as the hydrochloride salt. [α]⁵⁸⁹=+7.3 (c=0.6 inmethanol); ¹H NMR (CD₃OD) δ 2.21-2.38 (m, 3H), 2.60-2.66 (m, 1H),3.50-3.61 (m, 2H), 4.81-4.85 (m, 1H), 7.71-7.76 (m, 3H), 8.05 (d, J=8.2Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.26 (t, J=7.8 Hz, 1H).

Example 93(−)(S)-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

Example 93A (S)-tert-butyl2-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

Racemic EXAMPLE 50C (6.3 g) was resolved by chiral HPLC (Whelk 0,95:2.5:2.5 hexane/ethanol/methanol) to give the title compound as thefaster-diluting fraction (2.6 g, 100% e.e.), [α}⁵⁸⁹=−110.0 (c=0.65 inmethanol) and EXAMPLE 92A as the slower-diluting fraction (2.7 g, 97.5e.e.).

Example 93B(−)(S)-2-(2-fluoro-4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE92, substituting EXAMPLE 93A for EXAMPLE 92A. [α]⁵⁸⁹=−6.8 (c=0.7 inmethanol); ¹H NMR (CD₃OD) δ 2.22-2.37 (m, 3H), 2.60-2.65 (m, 1H),3.50-3.61 (m, 2H), 4.81-4.86 (m, 1H), 7.71-7.77 (m, 3H), 8.05 (d, J=7.6Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.26 (t, J=7.8 Hz, 1H).

The foregoing examples are meant to illustrate the invention but not tolimit it. Variations and changes obvious to one skilled in the art areintended to be within the scope of the invention as defined in theclaims.

1. A compound having formula (I)

or a salt thereof, wherein R₁, R₂, and R₃ are independently selectedfrom the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl,alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, nitro, NR_(A)R_(B), and (NR_(A)R_(B))carbonyl; each R₄ isindependently selected from the group consisting of hydrogen, halogen,alkyl, and haloalkyl; m is 4; Z is a bond or alkylenyl; A is

each R₅ is independently selected from the group consisting of alKenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano,haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl,heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, NR_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and (NR_(C)R_(D))sulfonyl; R₆ is selected from the group consisting ofhydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkyl, alkynyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl,hydroxyalkyl, (NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl,(NR_(C)R_(D))carbonylalkyl, and (NR_(C)R_(D))sulfonyl; (NR_(C) and R_(D)are independently selected from the group consisting of hydrogen, alkyl,and cycloalkyl; n is 0, 1, 2, or 3; and R_(A), R_(B), R_(C), and R_(D)are independently selected from the group consisting of hydrogen, alkyl,alkycarbonyl, and cycloalkyl.
 2. The compound according to claim 1having formula (I)

or a salt thereof, wherein R₁, R₂, and R₃ are independently selectedfrom the group consisting of hydrogen and halogen; each R₄ isindependently selected from the group consisting of hydrogen, halogen,and haloalkyl; m is 4; Z is a bond or alkylenyl; and R₆ is selected fromthe group consisting of hydrogen, alkoxycarbonyl, alkyl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocycle, and heterocyclealkyl.
 3. Thecompound according to claim 1, wherein Z is a bond. 4.-6. (canceled) 7.The compound according to claim 1 wherein R₁, R₂, and R₃ are hydrogen.8. The compound according to claim 1 wherein R₂ is halogen.
 9. Thecompound according to claim 1 wherein each R₄ is hydrogen.
 10. Acompound selected from the group consisting of:2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-methyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-ethylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-isopropyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-isopropyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-methyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-ethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-benzyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-phenethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;benzyl4-(3-(4-(4-carbamoyl-1H-benzimidazol-2-yl)phenyl)piperidin-1-ylmethyl)-1-carboxylate;2-(4-(1-(4-morpholin-4-yl-benzyl)piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-(4-piperidin-1-ylbenzyl)piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-piperidin-4-ylmethyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-ethyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;tert-butyl4-(4-(4-carbamoyl-1H-benzimidazol-2-yl)phenyl)piperidine-1-carboxylate;2-(4-(1-methyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-isopropyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-piperidin-4-ylmethylphenyl)-1H-benzimidazole-4-carboxamide;2-(4-(2-Piperidin-2-yl-ethyl)phenyl)-1H-benzimidazole-4-carboxamide;2-(2-fluoro-4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-isopropylpiperidin-4-ylmethyl)phenyl)-1H-benzimidazole-4-carboxamide;2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(2-fluoro-4-(1-isopropylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-piperidin-3-yl-3-trifluoromethylphenyl)-1H-benzimidazole-4-carboxamide;2-(2-fluoro-4-(1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;6-chloro-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-2-(2-fluoro-4-(1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-ethylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;6-fluoro-2-(2-fluoro-4-(1-isopropyl-piperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-cyclobutylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;6-chloro-2-(2-fluoro-4-(1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;6-chloro-2-(4-(1-ethylpiperidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;6-chloro-2-(4-(1-cyclopropylmethyl-piperidin-2-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-ethylpiperidin-3-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;2-(4-(1-cyclopropylmethylpiperidin-2-yl)-2-fluorophenyl)-6-fluoro-1H-benzimidazole-4-carboxamide;6-fluoro-2-(2-fluoro-4-(1-methylpiperidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide;6-chloro-2-(2-fluoro-4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;6-chloro-2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(2-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;6-chloro-2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-2-(4-piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide;2-(4-(1-ethylpiperidin-4-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;2-(2-fluoro-4-(1-isopropylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;6-chloro-2-(4-(1-cyclopropylmethylpiperidin-3-yl)-2-fluorophenyl)-1H-benzimidazole-4-carboxamide;6-Fluoro-2-(2-fluoro-4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;6-Chloro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-2-(4-(1-methylpiperidin-4-yl)phenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-4-(1-methylpiperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;(S)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;(R)-2-(2-fluoro-4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;6-fluoro-2-(4-piperidin-4-ylphenyl)-1H-benzimidazole-4-carboxamide;(S)-2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide;(R)-2-(4-piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide; and6-fluoro-2-(4-(1-methylpiperidin-3-yl)phenyl)-1H-benzimidazole-4-carboxamide.11. A composition comprising a compound having formula (I) of claim 1,or salt thereof, e and a therapeutically acceptable carrier.
 12. Amethod of treating inflammation in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formula(I), or salt thereof, of claim
 1. 13. A method of treating sepsis in amammal comprising administering thereto a therapeutically acceptableamount of a compound having formula (I), or salt thereof, of claim 1.14. A method of treating septic shock in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula (I), or salt thereof, of claim
 1. 15. A method oftreating cancer in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula (I) or asalt thereof.